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Research

2019 SCORE Pilot Projects

Jessica Alvarez

Jessica Alvarez, PhD Assistant Professor
Department of Medicine, Endocrinology,
Metabolism and Lipids Division
Emory School of Medicine

Use of High-Resolution Plasma Metabolomics to Determine Linkages Between Estrogen Induced Bone Loss and Intestinal Barrier in HIV


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.

Allison LoPilato

Allison LoPilato, PhD Assistant Professor
Department of Psychiatry and Behavioral Sciences
Emory School of Medicine

Sex Differences in the Risk Prediction of Serious Mental Illness


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.

Puja Mehta

Puja Mehta, MD Assistant Professor
Department of Medicine, Cardiology Division
Emory School of Medicine

Sex Differences in Coronary Microvascular Dysfunction


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.

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