Past Years

Associate Professor

Emory National Primate Research Center & Department of Pediatrics
Emory School of Medicine

2023 Add-An-Aim Grant Recipient
Base Grant: R01DA044297

INHIBITING P13K P110B TO BLOCK COCAINE - INDUCED HABITS AND DRUG SEEKING
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WHY SEX MATTERS IN SCIENCE:

...Because even though there are higher rates of drug misuse in men, women tend to progress to addiction more rapidly than males and women also experience higher rates of relapse following treatment. This suggests that processes controlling decision-making behavior (e.g., to seek drug or not) could differ between the sexes and we need to better understand potential sex-based physiological causes.

ABSTRACT

Using an animal (mouse) model, we recently discovered, while using site-selective in vivo gene silencing, that the cell adhesion receptor β1-integrin in the OFC is necessary for prospective, goal-directed action in male mice, but unexpectedly, females were resilient to β1-integrin loss5. Integrins are transactivated by Brain-Derived Neurotrophic Factor (BDNF) binding to its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and this transactivation is facilitated by estrogen6. We confirmed that stimulating TrkB in males made them appear "female" in their action selection strategies5. Potentially, TrkB-mediated control of goal-directed action is particularly potent in females.

With SCORE funding, we will ask the following questions: 1) Are females particularly reliant on TrkB in the mOFC for adaptive decision making? 2) Does neurotrophin-dependent action rely on input from the ventral hippocampus (vHC) (in both sexes)? These questions are important because stimuli like stressors and addictive drugs degrade neurotrophin systems in multiple cortical regions7,8,9. Further, TrkB-manipulating pharmacotherapies that augment cortical TrkB activity mollify addiction-related behavior in rodents and have been proposed as treatments in humans10,11, but their efficacy may differ between the sexes.

Assistant Professor

Hubert Department of Global Health
Rollins School of Public Health

2022 Add-An-Aim Grant Recipient
Base Grant: R01DK115937-03S2

DYNAMICS AND HEALTH CONSEQUENCES OF OBESITY BETWEEN INFANCY AND YOUNG ADULTHOOD IN THE UNITED STATES
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WHY SEX MATTERS IN SCIENCE:

...Because we do not yet know whether there are sex-base differences between boys and girls in the trajectories of height and weight gain and risk of incident obesity from childhood to adult ages.

ABSTRACT

Dual group-based trajectory modeling will be used to identify similar underlying trajectories of simultaneous height and weight gain from birth to age 35 for boys and girls separately. Group-based trajectory modeling is an individual-based, empirical approach that takes advantage of hierarchical modeling and latent growth curve modeling to analyze developmental trajectories and develop latent class growth curves. These models assume the population is made of unobservable subgroups that share similar growth trajectories and allow us to identify the trajectories and estimate the probability of trajectory membership.

Sex specific group-based trajectory models will be used first to estimate dual trajectories, adjusting for the effect of race/ethnicity, US Census region, level of urbanization and socioeconomic status. The second set of dual trajectory models will stratify by sex and race/ethnicity to examine different growth patters among White, Black, Hispanic, and Asian boys and girls (n=6strata/ sets of trajectories).

Once trajectories are identified, the posterior predicted probability (PPP) of being a member in each of the classes for each individual will be estimated. Participants will be assigned to the trajectory group for which they have the greatest PPP. Significant geographic predictors (rurality and regions) will be used to further examine the dual trajectories stratifying by significant geographic factors. These tests will allow us to recognize any potential differences in growth by sex that may be taking place at different geographic levels.

Outcomes from this study will expand the base grant project and introduce a current characterization of height and weight gain trajectories by sex and race/ ethnic group across different levels of urbanization and US regions.

Together, these studies will support the development of two grant applications: 1) The R21 application that will propose to expand the synthetic cohort to examine the dynamics of weight gain and neurodevelopmental trajectories from early life, and their association with cardiometabolic risks. 2) The R01 proposal aims to examine the etiology of cardiovascular disease risks and protective factors among children born to US and immigrant mothers using data from our synthetic cohort and additional datasets, and accounting for sex differences from birth.

Assistant Professor

Department of Cardiology
Emory School of Medicine

2022 Add-An-Aim Grant Recipient
Base Grant: R01HL140223

THE REGULATION OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) BY ADENOSINE IN MYOCARDIAL ISCHEMIA-REPERFUSION
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WHY SEX MATTERS IN SCIENCE:

... Because neutrophil extracellular traps (NET) formation has been shown to be associated with systemic lupus erythematosus, which is 9 times more common in women compared to men; with cardiovascular disease, which has more severe outcomes in women compared to men; and in other diseases which are more common or more severe in women but the the factors regulating NETosis are not well understood, especially in regards to biological sex differences between males and females.

ABSTRACT

Sex-based differences in diseases linked to NETosis are intriguing and hint at important mechanistic underpinnings. In fact, there are many differences in the immune system between males and females. In humans, females are less susceptible to viral infections such as influenza, hepatitis, and HIV but have more severe disease when infected. Females have higher expression of pattern recognition receptors, antiviral gene responses, and antibody and cell-mediated response to antigens and vaccines. Some of these differences are mediated by sex hormone receptors on immune cells influencing the transcription of cytokines and chemokines. Several key differences have been defined between male and female derived neutrophils. Neutrophils from males have markers of a more immature state including higher oxygen consumption and mitochondria. Female neutrophil have a higher type I interferon response signature, and important inflammatory pathway linked to anti-viral defense. Thus it is reasonable to hypothesize that there are male-female differences in NETosis.

As NET-related illnesses are more common in women, identifying sex-specific differences is key to identification of effective treatment strategies and surveillance diagnostic tests. These observations have led us to hypothesize the existence of sex-specific NET-regulatory pathways that could explain some of the burden of inflammatory diseases that differentially effect women. In this proposal, we will combine our expertise in neutrophil biology with sophisticated transcriptomic techniques to specifically investigate genes and pathways responsible for regulation of NETs in women.

Assistant Professor

Hubert Department of Global Health
Rollins School of Public Health

2022 Add-An-Aim Grant Recipient
Base Grant: OPP1191625 (Bill & Melinda Gates Foundation)

MEASURING URBAN SANITATION AND EMPOWERMENT (MUSE)
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WHY SEX MATTERS IN SCIENCE:

...Because heavy menstrual bleeding (HMB), defined as excessive blood loss leading to interference with the physical, emotional, social, and material quality of life of a woman, is a known risk factor for anemia but the relative contribution of HMB to the anemia burden in low- and middle-income countries has never been explored in detail.

ABSTRACT

No validated survey instrument exists for measuring HMB in LMICs. Instruments developed in high-income countries may not be suitable for use in LMICs given that many include references to sanitary products like tampons and disposable pads, which are not available or used by women in many LMIC settings. Many instruments are also overly time-consuming and/or complex, making them suitable only for clinical settings (6, 7). Therefore, the extent of HMB in LMICs remains largely unknown. A critical need exists for a validated survey instrument to measure HMB in LMIC settings, to define the prevalence of HMB among populations at highest risk of anemia.

With SCORE funding, the overall objective for this application is to validate a survey instrument that can be used in future studies to measure HMB and, in the process, to generate data on the prevalence of HMB across populations.

Assistant Professor

Department of Medicine (Cardiology)
Emory School of Medicine

2022 Pilot Grant Recipient

CHARACTERIZING SEX DIFFERENCES IN MALE AND FEMALE ZEBRAFISH HEART REGENERATION
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WHY SEX MATTERS IN SCIENCE:

... Because although sexual dimorphism seems to exist in heart diseases and repair, a mechanistic understanding of this sex difference is still lacking. Deciphering the mechanisms of sex differences will provide an important gateway toward better prevention and treatment of cardiovascular disease in women.

ABSTRACT

Humans, like all mammals, possess a limited myocardial regeneration capacity. This deficiency contributes to heart failure, the leading cause of morbidity and mortality in the United States. Recent discoveries indicate that mammalian heart has an endogenous regeneration program but cannot efficiently initiate or complete the entire process. Fully deciphering cardiac regeneration mechanisms will promote therapeutic strategies to prevent or treat human heart failure. Zebrafish robustly regenerate lost myofibers by proliferating spared cardiomyocytes (CMs). This process is facilitated by other cell types, like epicardial and immune cells, representing an excellent model to explore heart regeneration.

In preliminary studies, we employed bulk RNA-seq and in situ hybridization analyses to examine gene expression in male and female regenerating hearts, and found the expression levels of 258 genes have sex differences in regenerating hearts, including the f13a gene. With a newly generated f13a:EGFP BAC transgenic reporter, we visualized few f13a:EGFP+ cells in uninjured female hearts but they rapidly accumulate in the injury area. In contrast, no f13a:EGFP+ cells appear in male hearts with or without injury. Further examination of f13aexpressing cells with immunohistology and our unpublished single-cell RNA sequencing dataset suggested that f13a+ cells are immune cells. As immune cells play critical roles in heart repair and regeneration, characterizing sex-specific immune cells will be essential for understanding regeneration differences in male and female hearts.

Based on our preliminary results, our hypothesis for this proposal is that f13a+ cells and the f13a gene are critical components for the enhanced heart regeneration capacity observed in females. To test this hypothesis, we will: 1) perform single-cell RNA sequencing to obtain a molecular profile of f13a+ cells; 2) establish genetic methods to specifically deplete f13a+ cells and examine the effect of their loss on female heart regeneration; and 3) examine the effect of f13a knockout on female heart regeneration.

As female-specific cell types/genes haven't been identified in the zebrafish heart before, our work will generate paradigm-shifting sex difference discoveries in cardiac regeneration biology, and reveal the impact of sex-specific cells and genes on heart regeneration. These findings will reveal new approaches for sex difference research in zebrafish, and potentially enhance research on human hearts after myocardial infarction.

Professor

Department of Cell Biology
Emory School of Medicine

2022 Pilot Grant Recipient

ELEVATED VULNERABILITY IN FEMALE AND AGING POPULATIONS TO LONG-TERM DEFICITS AND DEGENERATION AFTER MILD HEAD TRAUMA
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WHY SEX MATTERS IN SCIENCE:

...Females tend to demonstrate a course of outcome and recovery from mild traumatic brain injury that is different than the ones males experience but we do not yet understand how or why this is so. If we can unravel how the mechanistic underpinnings of early exposure to mild head trauma lead to later brain degeneration and disability, we may be able to develop therapeutic strategies for treatment and recovery that are optimized for women.

ABSTRACT

Increasing evidence supports the existence of sex-related differences in many medical conditions, including several neurodegenerative disorders, but the underlying mechanisms remain to be fully understood.

Traumatic brain injury (TBI) is extremely common and represents a great risk for long-term brain disability and can accelerate the progressive neurodegeneration. In particular, repetitive exposure to mild TBI is believed to set in motion often latent pathologic processes that can later emerge in association with a number of disorders that include Chronic Traumatic Encephalopathy (CTE), Alzheimer's disease (AD), Parkinson's disease like disorders, and other associated progressive neurodegenerative conditions. At presence, we unfortunately lack the mechanistic understanding of how early exposure to mild head trauma leads to later emergence of brain degeneration and disability.

Importantly, sex is known to be an important biological variable that influences the outcome of TBI of various severities. However, it remains to be determined if and how different sexes of individuals respond to mTBI with different outcomes and, importantly, whether the later development of brain deficits is more prevalent in one sex over the other. Finally, emerging evidence indicates that age represents a major risk factor that can significantly impact and contribute to the long-term brain deficits after head injury. It is of great importance to understand how If and how aging affects sex differences in response to mild head injury, subsequent recovery, and the development of long-term deficits later in life.

We recently developed a novel head injury model in Drosophila melanogaster to investigate the long-term effects of mild head trauma on brain structure and function, as well as the underlying mechanisms. Fruit flies represent an excellent tractable model organism to dissect fundamental cellular and molecular disease mechanisms, including neurodegeneration. Importantly, the relatively short lifespan of fruit flies enables longterm outcome analyses related to head injury exposure.

We have already shown that adult fruit flies subjected to repetitive mild head trauma developed long-term sensorimotor deficits and brain degeneration, all of which were substantially exacerbated in female flies (Behnke et al, Sci Reports 11:9738, 2021). In this study, we will utilize our novel Drosophila head injury model to fully investigate the sex differences in developing brain deficits and degeneration after mild head trauma.

Importantly, we will investigate how aging impacts the brain deficits in a sex-dependent manner in response to mild head trauma. Finally, we will perform an unbiased transcriptome analysis to identify the transcriptional changes associated with the later emergence of brain dysfunction and deficits. Our goal is to use the model organism and the novel head trauma model to gain mechanistic insights into the development of brain disorders triggered by head trauma.

Professor

Department of Hematology and Medical Oncology
Emory School of Medicine

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Assistant Professor

Department of Pediatric Infectious Diseases
Emory School of Medicine

2022 MPI Pilot Grant Recipients

SEX BIAS IN STING SIGNALING AND DOWNSTREAM FUNCTIONS OF LUNG-INFLITRATING NEUTROPHILS AS A KEY CONTRIBUTOR TO DISEASE SEVERITY AND DRUG RESPONSE
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WHY SEX MATTERS IN SCIENCE:

... Because there are strong sex-biased outcomes in lung cancer but, because we don't understand why, we don't know how to overcome them.

ABSTRACT

The LKB1/STK11 tumor suppressor is one of the most frequently mutated genes in smoking-related lung adenocarcinoma (LUAD). A multidimensional analysis of LUAD patients indicates that STK11/LKB1 is the top sexbiased gene, being more frequently mutated in males than in females. This is a surprising discovery because LKB1 is mostly mutated in smoking-relative lung cancer, and previous sex-specific studies indicated that females are more prone to smoking-related DNA adduct formation in the lungs.

Several established mouse models also suggested the female sex is associated with a higher incidence of lung cancer formation. Thus, there is an urgent need for the development of new treatments using clinically relevant mammalian models. The Zhou laboratory and other groups established genetically engineered mouse models (KL-GEMM), which can form KrasG12D/LKB1null LUAD in the lung with similar features to human LUAD in tumor characteristics, microenvironment, and resistance to immune checkpoint blockade therapy.

A meta-analysis of the model revealed LUAD formation in 97% of males vs. 58% of females. In addition, the establishment of lung metastases in this syngeneic model also showed a strong sex bias in females. A decrease in tumor growth is also observed in female nude mice, but not in NSG mice. Since nude mice lack T- and B-cell immunity but retain innate immune function while NSG mice lack all, these data suggest innate immune cells play a role in this process.

Independently, the Tirouvanziam laboratory has investigated the ability of neutrophils, the most abundant subset of innate immune cells, to adopt novel functional fates upon recruitment to the human lung. Chronic recruitment of neutrophils is a key event in lung cancer, notably in LKB1/STK11-driven LUAD. Our work unveiled profound transcriptional and functional reprogramming in lung-recruited neutrophils involving the methyltransferase Enhancer of zeste homolog 2 (EZH2). EZH2 is a direct target of LKB1 and a regulator of stress responses mediated by STING, the major sensor of cytosolic DNA that regulates pathogen and cancer recognition. Interestingly, recent studies have shown strong sex bias in neutrophil-mediated STING signaling.

Based on the above data, we hypothesize that sex-biased STING signaling and downstream functions in recruited neutrophils may be responsible, at least in part, for the sex-biased outcomes in lung cancer. To test this hypothesis, we will pursue two pilot aims: 1 – Quantify differences in STING signaling and downstream functions in neutrophildominated lung cancer based on sex; 2 – Evaluate the response to EZH2- and STING-targeted drugs in neutrophildominated lung cancer based on sex. Successful completion of this pilot study will pave the way for a comprehensive, joint R01 proposal focused on sex differences in neutrophil modulation of primary and metastatic lung cancer, to be submitted to NCI in 2023.

Assistant Professor

Yerkes National Primate Research Center

ASSESSMENT OF BIOLOGICAL SEX-BASED DIFFERENCES IN NATURAL KILLER CELL FC RECEPTOR EXPRESSION AND FUNCTION IN THE RECTAL MUCOSA
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WHY SEX MATTERS IN SCIENCE:

...Because we do not yet know whether there are sex-based differences in the way that the immune system responds to the detected presence of HIV in rectal tissue.

ABSTRACT

A preventative vaccine is urgently needed to reduce the global burden of new HIV infections. A leading strategy for preventing HIV infection is the induction of antibodies directed to the viral envelope glycoproteins. The protective efficacy of anti-HIV antibodies has been demonstrated in a clinical trial of a human HIV vaccine candidate and in the non-human primate (NHP) model of HIV exposure. Antibody-conferred protection from HIV is mediated through viral neutralization and the elimination of antibody-opsonized viral particles and infected cells through antibody Fc-dependent functions, such as antibody-dependent cellular cytotoxicity (ADCC).

ADCC is mediated by effector cells following the ligation of cell surface Fc receptors (FcR) by antibody bound to the surface of infected cells. Our current understanding of anti-HIV ADCC has primarily been established through in vitro assays using effector cells derived from peripheral blood. Natural killer (NK) cells are major and well characterized mediators of ADCC within peripheral blood. As HIV exposures primarily occur at anogenital mucosae, it is important to determine the frequency and Fc-dependent functional potential of mucosal NK cells. In recent experiments, we observed FcR-expressing NK cells within rectal biopsies collected from macaques, an NHP commonly used in models of HIV exposure. The capacity of rectal FcR-expressing NK cells to mediate anti-HIV antibody Fc-dependent functions has not yet been assessed.

An important variable to consider for assessments of NK cell frequency and function is biological sex. The frequency and cytotoxic potential of peripheral blood and lymphoid tissue NK cells has been shown to be higher in biological males. In the current proposal, we will conduct the initial assessment of the impact of biological sex on the frequency and function of FcR-expressing NK cells within the macaque rectal mucosa. We hypothesize: (1) the frequency of FcR-expressing NK cells will be higher in the rectal mucosa of male macaques compared to females; and (2) the Fc-dependent functions of FcR-expressing NK cells will be higher in the rectal mucosa of male macaques compared to females.

In Aim 1, we will assess the impact of biological sex on the frequency of FcR-expressing NK cells within the rectal mucosa. The proposed experiments will confirm the presence of FcR-expressing NK cells in the rectum and determine if biological sex influences their frequency.

In Aim 2, we will assess the impact of biological sex on the anti-HIV Fc-dependent functions of rectal FcRexpressing NK cells. These experiments will determine the capacity of rectal FcR-expressing NK cells to mediate Fc-dependent functions and the impact of biological sex on this capability.

The proposed research is an important step towards designing HIV vaccine strategies that specifically engage immune cells present within anogenital mucosae and confer protection from HIV across biological sexes.

Instructor of Medicine

Renal Division
Department of Medicine
Emory School of Medicine

SEX DIFFERENCES AND HYPERTENSION: EFFECTS ON NMDA RECEPTORS
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WHY SEX MATTERS IN SCIENCE:

...Because even though women experience a protective effect from high blood pressure (hypertension) -- which, if untreated, is the main cause of heart attack, stroke, and the need for dialysis -- during their fertile age, their risk for hypertension increases dramatically, even more so than in men, in their postmenopausal period and we don't know why.

ABSTRACT

Hypertension is the leading single risk factor for mortality worldwide. However, in more than 90% of hypertensive patients, the cause is unknown. There is sex differences in hypertension prevalence. Thus, women has a relative protection for hypertension in the fertile age. However, this difference disappears in the post menopause period and after 70 years old, women have a higher hypertension prevalence. The sex difference in hypertension is not very well understood and estrogen has been found to play a role on the pathogenesis of hypertension. Thus, there is a need to understand the complex mechanisms associated with postmenopause hypertension and the role of estrogens, in order to develop more personalized treatment for women.

Connecting tubule-glomerular feedback (CNTGF) is kidney feedback mechanism that facilitates sodium excretion under certain physiological situations by inducing vasodilation. It has been previously demonstrated that e N-methyl-D-aspartate receptors (NMDAr) can induce renal vasodilation by sensitizing the CNTGF. Dr. Romero's long-term objectives are to explore the consequences of impaired vasodilation in the kidney as a cause of hypertension and develop a program to thoroughly understand some of the causes of human hypertension.

The main hypothesis of the current proposal is that estrogen increase the function of NMDAr favoring sodium and water excretion and that the lack of estrogen down regulates NMDAr inducing hypertension, explaining part of the sex differences observed in hypertension, specially in postmenopause period. The hypothesis will be addressed through the following specific aims: AIM 1: To determine the effects of estradiol on BP and NMDA receptor expression in the kidney. We hypothesized that estradiol will increase NMDA receptor expression in the kidney and decrease blood pressure. We will use neutered male mice infused with estradiol or vehicle and compare NMDAr expression, function, and signalin. Blood pressure and renal hemodynamic will also be compared between the groups. AIM 2: To evaluate the protective effect of NMDA receptors in hypertension in post-menopause mice. We hypothesize that an NMDA agonist will prevent hypertension development in post-menopause females. We will use the accelerated ovarian failure (AOF) mice model induced by 4-vinylcyclohexane diepoxide injection in a model of angiotensin II-induced hypertension. We will treat the AOF hypertensive females with NMDA potentiator or vehicle. Four groups will be compared. The primary outcome will be blood pressure level. Secondary outcomes will be RFR and NMDA expression. Dr. Romero will be guided by Dr. Eaton as a principal mentor as well as Dr. Reckelhoff as co-mentor. Overall, this proposal will allow us to explore deep causes of post-menopause hypertension and contribute to the scientific advances on woman's health. In addition, this pilot funding will allow us to open a new line of research in sex differences in hypertension, for future grant submission.

Assistant Profesor

Department of Cell Biology
Emory School of Medicine

ENHANCING AXON REGENERATION WITH SEX-DEPENDENT EXERCISE THERAPIES
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WHY SEX MATTERS IN SCIENCE:

... Because males and females experience enough differences in the way their bodies work to repair nerve damage following injury that there may be benefits to designing sex-differentiated exercise protocols that promote nerve regeneration. 

ABSTRACT

Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. Nerve injuries significantly impact the long-term quality of life, and many injured individuals seek continued life-long treatments for associated disabilities and pain. The common reason given for the poor functional outcomes is the process of axon regeneration. Over the past decade, our laboratory has shown that exercise strikingly enhances peripheral axon regeneration and significantly improves functional recovery following complete nerve. However, the translational potential of exercise has limitations. Many patients are not candidates for exercise due to issues, such as co-morbidities that preclude rehabilitation, necessary immobilization of a limb following surgical nerve repair, unknown dose requirement of exercise and patient compliance. We propose here to investigate a novel signaling mechanism (hypoxia inducible factor 1, HIF1) to promote sensory, motor, and sympathetic axon regeneration.

Based on the literature, we suggest that HIF1α may be the key mediator of how exercise robustly promotes axon regeneration after nerve injury. The HIF complex controls the transcription of numerous genes associated with neurogenesis, neuronal survival, neuronal metabolism, and angiogenesis. De-regulation of HIF1α has been identified in several neurodegenerative diseases (e.g., amyotrophic lateral sclerosis) and neural injuries (e.g., spinal cord injury and stroke). Notably, neuronal HIF1α was shown to be required for axon regeneration after peripheral nerve injury.

With pilot data, we show that the exercise protocol we have shown to enhance axon regeneration after sciatic nerve injury upregulates HIF1α in axotomized motoneurons. We also show that by pharmacologically stabilizing HIF1α, axons also elongate even farther than after treatment with exercise. This suggests that optimizing HIF1α signaling may lead to better regeneration and functional recovery. The goal of this study will be to investigate the fundamentals of stabilizing HIF1α by sex-dependent exercise protocols in axotomized neurons to treat peripheral nerve injuries in males and females.

Assistant Professor

Nell Hodgson Woodruff School of Nursing

SEX DIFFERENCES IN INFLAMMATORY CORRELATES OF HEART FAILURE SYMPTOMS
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WHY SEX MATTERS IN SCIENCE:

...Because we do not yet understand the inflammation-related physiological underpinnings anchoring the clinical reality that men and women experience heart failure differently, with women suffering significantly higher symptom burden, morbidity, and mortality.

ABSTRACT

Heart failure (HF) is a progressive, terminal illness with frequent decompensation related to ventricular remodeling. Because HF remains a leading cause of morbidity and mortality in the United States, identification of novel therapeutic targets that may slow disease progression are urgently needed. There are significant sex differences in HF clinical course and outcomes, with morbidity and mortality significantly higher in women than in men. These differences have been linked to differences in inflammation. Women develop HF later in life than men, and thus have a difference clinical course them men. Inflammatory burden increases with age and promotes the development of cardiovascular disease. Previous studies suggest that sex may moderate the relationship between inflammation and depressive symptoms in cardiometabolic disease, but the relationship in HF is unknown. Adequate symptom management in HF requires both comprehensive symptom assessment and sufficient knowledge of available approaches to alleviate symptoms related to both HF and common comorbidities. Thus, understanding the physiological underpinnings of physical symptoms (i.e. fatigue) and emotional symptoms (i.e. depression) can direct treatment strategies. However, few studies have found significant associations between symptoms and objective physical or psychological measures in HF. Further understanding of the underlying mechanisms of each symptom in persons with HF and the role of comorbidities is needed. This proposal adds an exploratory sub-study to an ongoing pilot study, currently in progress, that examines symptoms and metabolomic pathways in Black adults with HF. Thus, this study addresses the disparities in morbidity and mortality experienced by two at-risk populations by examining sex differences in inflammation and the symptoms of depression and fatigue in Black adults living with HF. By examining sex as a biological variable in the relationship between inflammation and symptoms in HF, this study will advance our understanding of symptoms and address the gaps in knowledge that will lead to more precise symptom-reducing interventions in HF.

Assistant Professor

Department of Environmental Health
Rollins School of Public Health

SEX-SPECIFIC GENETICS OF SALT SENSITIVITY IN FAMILIES FROM SOUTHWEST COASTAL BANGLADESH
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WHY SEX MATTERS IN SCIENCE:

...Because even though rising sea levels are changing the salinity of ground water in coastal communities, potentially leading to increases in hypertension among salt-sensitive people, very little is known about the extent that genetic influences by sex play in the biological response to salts that can affect blood pressure.

ABSTRACT

Salt sensitivity is thought to play an important role in blood pressure, and there are likely biological sex differences in salt sensitivity. Salt exposures in many coastal communities are changing as a consequence of sea-level rise and adaptation attempts to blunt the harms of that climate change impact. The purpose of this SCORE pilot is to leverage data from a climate change adaptation trial in southwest coastal Bangladesh, which diluted groundwater and reduced exposure to a number of salts including magnesium, calcium, sodium, and potassium, to better understand biological sex differences in response to salts for blood pressure, in particular genetic influences by sex. This work involves application of novel approaches to gene-environment interactions, which could be more broadly useful across scientific applications.

Assistant Profesor

Department of Psychiatry and Behavioral Sciences
Emory School of Medicine

DYSREGULATED EATING AND INFLAMMATION IN WOMEN AND MEN WITH AND WITHOUT PTSD
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WHY SEX MATTERS IN SCIENCE:

... Because despite the fact that dysregulated eating is more prevalent in women, and women are more likely to develop PTSD following trauma exposure, sex differences in dysregulated eating or inflammation have not been examined in those with vs. without PTSD diagnosis. 

ABSTRACT

Increased systemic inflammation is characteristic of obesity and cardiometabolic dysfunction, and has been linked to posttraumatic stress disorder (PTSD) diagnosis presence and severity. Although rates of cardiometabolic dysfunction are similar in women and men, women have higher mortality rates from these conditions. Women also have higher rates of PTSD diagnosis. Dysregulated eating behaviors include binge eating and behaviors traditionally associated with substance misuse (i.e., food addiction), and are more prevalent in the general population than threshold eating disorders. They also have been shown to be more prevalent among those with trauma histories compared to those without. Dysregulated eating behaviors, even when not meeting full threshold for eating disorders diagnosis, contribute to obesity and metabolic dysfunction. Compared to men, women have higher prevalence of dysregulated eating, including food addiction (FA). However, we do not know to what extent FA is associated with PTSD diagnosis or inflammation severity, and whether there are sex differences in these relationships. Therefore, the aims of this study include examining the combined effect of sex and PTSD diagnosis on FA severity (Aim 1) and inflammation severity (Aim 3), and examining the combined effect of sex and FA diagnosis on inflammation severity (Aim 2) in post-9/11 women and men veterans seeking treatment for PTSD, anxiety, or depression. We hypothesize that women with PTSD will report significantly higher FA severity compared to the other groups (i.e., women without PTSD, men with PTSD, men without PTSD) and that women with FA will report the highest inflammation severity compared to other groups (i.e., women without FA, men with FA, men without FA). We will also explore the inflammatory profiles of women and men with and without PTSD. The proposed study is innovative because the relationships between FA and PTSD diagnosis or FA and inflammation have not been examined. It is also innovative in the recruitment of a veteran sample, a population in which eating behaviors have been understudied, despite rates of obesity and metabolic dysfunction similar to the general population. The results from this study will provide empirical basis for examining the efficacy of a combined/concurrent PTSD and eating dysregulation intervention on PTSD symptoms, eating dysregulation behaviors, and metabolic syndrome components. By understanding the biological and psychological correlates of dysregulated eating, we have the potential to develop effective and efficient behavioral interventions that concurrently target emotional and dysregulated eating symptoms, and putatively, the neuroendocrine and immune systems.

Assistant Profesor

Department of Epidemiology
Rollins School of Public Health

STRESS AND OVARIAN AGING ON CARDIOVASCULAR RISK
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WHY SEX MATTERS IN SCIENCE:

... Because coronary heart disease (CHD) is the number one cause of death among women. Women with CHD have less obstructive coronary artery disease yet greater risk of myocardial ischemia compared with similarly aged men and there is growing recognition that emotional stress and physiological sex differences in response to stress are important in women's cardiovascular vulnerability. There is a higher burden of psychosocial factors including depression, early life adversity, posttraumatic stress disorder (PTSD), poverty and neighborhood disadvantage among women than men with CHD. In addition to having a greater prevalence of psychosocial stressors, women may be more vulnerable to the adverse effects on stress/mental health on CHD, risk as shown in prior research. Several studies have suggested that women with CHD are at higher risk of adverse cardiovascular outcomes than men in the presence of psychosocial exposure. 

ABSTRACT

The purpose of this SCORE pilot proposal is to provide preliminary data and new training on stress and sex hormone biology to understand mechanisms of sex differences in cardiovascular disease and potential disparities among women. The premise of this research project is based on the applicant's own research which suggest that compared to men of similar age, women (and particularly, younger women) with coronary heart disease have distinct vascular mechanisms in relation to stress and myocardial ischemia, and have higher basal and stress-related inflammation, and are more likely to develop myocardial ischemia during mental stress. The underlying explanation for these sex differences is unknown; however, one potential mechanism involves sex hormone biology among premenopausal women and across the menopausal transition. Stress may impair female reproduction through diminished ovarian reserve and induce earlier age at menopause, which have been associated with cardiovascular risk, possibly through sex hormone-related pathways influencing immune response, vascular, and cardiac function. The overall goal of this project is to understand mechanisms for sex differences in inflammatory and vascular responses to mental stress, and the role of ovarian function and menopausal status among women. The applicant will leverage the infrastructure of the Myocardial Infarction and Mental Stress Study 2 (MIMS2: R01HL109413), which was recently renewed for a new enrollment wave with the same methods (MIMS3: 2R01HL109413). The two waves will eventually total 300 women with a recent MI, ≤ 60 years of age (mean and median age 50 yr). All data for MIMS2 is currently completed including data on anti-Müllerian Hormone (AMH), a biomarker of ovarian reserve and menopausal status in women on 150 MI women and 58 age-matched community controls. During the first year of recruitment for MIMS3 (expected start date of Jan. 2020), an additional 30 MI women and 30 controls will be enrolled, allowing the applicant to collect additional AMH assays on these participants and obtain a larger sample size, achieving a combined total of 180 MI women and 88 controls from MIMS2 and MIMS3 for this pilot project. The scientific aims of this project are to: 1) Examine differences in gonadal aging and age at menopause between women with MI and age-matched control women; 2) Examine whether gonadal aging (lower AMH levels) is associated with greater inflammation and vascular response to mental stress among women with MI compared to age-matched control women; and 3) Examine whether psychosocial stressors (e.g., depression, early life adversity, discrimination, and socioeconomic disadvantage) are associated with gonadal aging (lower AMH levels) among women with a recent MI and age matched controls. The new enrollment of patients and controls will provide key opportunities for training and data collection on gonadal aging and vascular function to inform the development of future NIH-R01 proposals.

Profesor

Nell Hodgson Woodruff School of Nursing

DO MECHANISMS OF FATIGUE AFTER ATRIAL FIBRILLATION ABLATION DIFFER BY SEX?
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WHY SEX MATTERS IN SCIENCE:

... Because Over 6 million patients in the U.S. have atrial fibrillation (AF), the most common irregular heart rhythm, effectively treated by AF ablation but sex-linked differences that would enable physicians to potentially predict which AF patients are at highest risk of fatigue and/or negative ablation outcomes have not yet been studied. 

ABSTRACT

The goal of the proposed research is to determine whether increased fatigue following cardiac ablation therapy for atrial fibrillation (AF) is associated with increased inflammation and to test whether differences exist by sex. AF is the most common, costly cardiac arrhythmia affecting over 6 million people in the U.S. and a major public health problem with a 2-fold increase in mortality. No cure exists for AF, but our best treatment to improve quality of life is AF ablation (AFA). From our prior pilot study, patients reported severe fatigue that can last up to three months after AFA treatment, negatively affecting quality of life. In order to prevent this trajectory, it is critical to identify those patients at highest risk so that evidence based interventions can be developed and tested. Understanding the characteristics and mechanisms of fatigue is critical to its successful management and the development of targeted therapies. In cancer and HIV, fatigue has been documented to occur as a response to inflammation associated with elevated inflammatory (cytokines, high sensitivity C-reactive protein) and oxidative stress markers. These biomarkers have not been studied in relation to AF symptoms such as fatigue. The long-term goal of this research is to identify mechanisms of AF-related fatigue using inflammatory and oxidative stress markers and to investigate whether there is an interactive effect of inflammatory factors by sex on fatigue. Thus, this study will compare levels of AF-related fatigue, and inflammatory and oxidative stress markers, in 20 AFA subjects (10 men, 10 women) pre- and post-AFA (at time points of baseline [pre-AFA], and at 1 and 3 months post-AFA). Patients will have biomarkers drawn and complete symptom questionnaires at each measurement point. Patients will also wear a cardiac patch monitor for two weeks at each time point to measure sleep, fatigue, and amount of AF versus normal rhythm. Understanding characteristics and mechanisms of AF fatigue and identification of potential outcome endpoints are critical to successful identification of those at highest risk of negative outcomes. Addressing these aims will identify fatigue patterns and biomarkers to be used in a subsequent R01 proposal to develop and test targeted interventions to improve outcomes in high-risk adults with AF.

Assistant Professor

Division of Endocrinology, Metabolism, and Lipids
Department of Medicine
Emory School of Medicine

USE OF HIGH-RESOLUTION PLASMA METABOLOMICS TO DETERMINE LINKAGES BETWEEN ESTROGEN INDUCED BONE LOSS AND INTESTINAL BARRIER IN HIV
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WHY SEX MATTERS IN SCIENCE:

... Because HIV-induced bone loss may be particularly significant in older women due to exacerbated fracture risk from loss of estrogen.

ABSTRACT

With improved medical care, including the introduction of successful antiretroviral therapies (ART), the age demography of HIV/AIDS has shifted so that it is projected that over half of all individuals living with HIV are now over 50 years old. A new landscape of HIV is now apparent, with a high rate of age-related comorbidities that are exacerbated by HIV infection and side effects of ART. Bone loss and resulting osteopenia/osteoporosis and bone fracture risk are alarmingly high in individuals with HIV, especially postmenopausal women where both estrogen deficiency and HIV infection/ART contribute to inflammation induced bone loss. Recent research implicates dysregulation of the gut microbiome and increase in gut mucosal permeability (“leaky gut”) causing influx of inflammatory mediators, such as lipopolysaccharide (LPS), as contributors to bone loss. By contrast, a healthy microbiome can protect against bone loss via production of bacterial-derived short chain fatty acids (SCFA) that stimulate bone formation (bone anabolic). Furthermore, studies suggest that estrogen deficiency and HIV infection both independently contribute to loss of gut barrier integrity. The specific interactions between gut permeability, estrogen deficiency, and HIV-infection are, however, not known. We hypothesize that bone loss in women with HIV infection is due, in part, to gut dysbiosis driving imbalance between bone catabolic and bone anabolic bacterial metabolites, and exacerbated by estrogen insufficiency/deficiency. Recent advances in high-resolution metabolomics (HRM) provide a unique opportunity to broadly explore metabolism and underlying pathways relevant to HIV and women’s health. The purpose of this SCORE pilot study is to use plasma HRM with advanced bioinformatics to interrogate the interrelationships between circulating gut-bacterial derived metabolites, bone mineral density (BMD) and biomarkers of bone formation and loss, and estrogen deficiency in women living with HIV. Aim 1 will assess the association of circulating bacterial-derived metabolites and HIV status with bone turnover and BMD, while Aim 2 will assess the interactions of estrogen on these relationships. The overall goal of this project is to obtain new insight into HIV- and estrogen deficiency-induced bone loss that will inform the design of future interventions to reduce the risk for osteoporosis and fracture among women living with HIV. This SCORE grant will provide outstanding preliminary data for subsequent NIH R-level studies focusing on the pathophysiology of bone disease among women living with HIV and the development of new strategies to improve health and quality of life in this aging population.

Assistant Profesor

Department of Psychiatry and Behavioral Sciences
Rollins School of Public Health

SEX DIFFERENCES IN THE RISK PREDICTION OF SERIOUS MENTAL ILLNESS
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WHY SEX MATTERS IN SCIENCE:

... Because clinical risk prediction models for serious mental illness (e.g., schizophrenia, bipolar disorder) have not yet included sex as a variable of interest. This is a surprising and critical omission, given that sex differences are widely observed in the clinical presentation, functional outcome, and neuroanatomy of individuals with serious mental illness. Additionally, most SMI samples have a larger proportion of males, which may obscure risk markers of greater relevance to females when sex is not taken into consideration. Although this compromises risk prediction for both sexes, females are disproportionally affected. A better understanding of sex differences in clinical risk profiles, and the integration of sex into prediction model development, will improve the effectiveness of our risk prediction tools and early interventions for both men and women.

ABSTRACT

Early identification and preventative interventions are the key to ameliorating the personal, social, and economic burden associated with serious mental illness (SMI). Accurate risk prediction models that can identify individuals prior to illness onset are critical to these early intervention efforts. Over the past two decades, clinical high risk (CHR) research designs have identified risk markers that predict conversion to SMI. These risk markers have been used to develop prediction models that estimate an individual’s likelihood of developing SMI based on their risk profile. However, research on these approaches has only recently been conducted, and has not yet included sex as a variable of interest. This is a critical omission, given that sex differences are widely observed in the clinical presentation, functional outcome, and neuroanatomy of individuals with SMI. The current project will systematically evaluate and incorporate sex differences into clinical risk prediction models for serious mental illness (SMI). The limited investigation of sex differences in CHR research is a serious problem for the power and utility of current risk prediction tools. To address these concerns, we will utilize data from the North American Longitudinal Prodromal Study (NAPLS), the largest CHR study to date (n=764) to: 1) identify sex differences in risk predictors, 2) examine sex differences in the performance of the current NAPLS risk calculator, and 3) test whether prediction can be improved by developing sex specific models. A better understanding of sex differences in CHR risk profiles, and the integration of sex into prediction model development will improve the effectiveness of our risk prediction tools and early interventions.

Assistant Profesor

Division of Cardiology
Department of Medicine
Emory School of Medicine

SEX DIFFERENCES IN CORONARY MICROVASCULAR DYSFUNCTION
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WHY SEX MATTERS IN SCIENCE:

... Because although Coronary Microvascular Disease is a clinical problem that disproportionately affects women, previous research on high-risk plaque features that would indicate vulnerability to CMD has not taken sex as a biological variable into account. 

ABSTRACT

Approximately two-thirds of women with chest pain who are suspected of having myocardial ischemia and undergo coronary angiography are actually found to have no obstructive coronary artery disease (CAD) (<50% luminal stenosis). Evidence over the past two decades indicates that coronary microvascular dysfunction (CMD) may be an explanation in such cases. CMD is associated with an adverse cardiovascular prognosis and an estimated 3 million women are impacted by CMD. Ischemic heart disease risk factors (such as hypertension, dyslipidemia, insulin resistance, and estrogen loss) promote a pro-inflammatory, pro-oxidative state which is associated with CMD. Our preliminary data show an increase in inflammation/oxidative stress in CMD. It is unclear whether abnormal microvascular function in these patients is independent of epicardial plaque burden, albeit it is non-obstructive CAD. Furthermore, sex-differences in high risk plaque features (HRP) that would indicate vulnerability have not been investigated in CMD. HRPs can be detected reliably and efficiently by coronary computed tomography angiography (CCTA) using a low radiation exposure protocol. We hypothesize is that compared to men, women with CMD have more HRP features. We further hypothesize that this difference will be reflected in increased systemic inflammation/oxidative stress in women. To support this hypothesis, the PI proposes to collect pilot data in 28 subjects (ages ≥ 50 years) to study HRP features by CCTA in those diagnosed with CMD compared to non-CMD controls. CMD is diagnosed by a low coronary flow reserve of <2.0 (n=14). Controls will include subjects with a normal coronary flow reserve ≥ 2.0 (n=14). Each group will have an equal number of men and women. We will only include post-menopausal women in this pilot proposal. The findings from this proposal will support an R01 application submission next year to study sex-differences in CMD.