Main content

Research

2021 - 2022  SCORE Pilot Projects

Matthew Parsons

Matthew Parsons, PhD 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


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 wellcharacterized 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.

Cesar Romero

Cesar Romero, MD, PhD Instructor of Medicine
Department of Medicine, Renal Division
Emory School of Medicine

Sex Differences and Hypertension: Effects on NMDA Receptors


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 ourcomes 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.

Jill Ward

Jill Ward, PhD Assistant Professor
Department of Cell Biology
Emory School of Medicine

Enhancing Axon Regeneration with Sex-dependent Exercise Therapies


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.

Subscribe to the SCORE Newsletter

Stay informed about new research, funding opportunities, and events.