Chronic pain is a debilitating condition that affects all segments of the population. It is now recognized that there are clear differences between males and females in the biological mechanisms associated with chronic pain. It has been shown that immune cells play a major role in mediating pain central sensitization in the spinal cord, which is a major step in the transition from acute to chronic pain. Interestingly, microglia are the immune cells active in central sensitization in males, while T-cells play a more active role in females. Unfortunately, the majority of pain research in the past has been done on male rodents. In this pilot project, the investigators seek to develop a sex-specific model of pain central sensitization which will be bioengineered from human stem cells. The models will consist of peripheral nerve cells in synaptic communication with spinal cord cells, including microglia. Both male and female versions of the model will be constructed, and the electrophysiological responses to inflammatory stimuli will be compared. With the establishment of sex specificity, this model will be poised to measure sex differences in chronic pain using human cells and to enable a precision-medicine approach to the identification of effective therapeutics.

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Sleep loss disrupts the precise orchestration of circadian clocks and elevates both nocturnal and daytime blood pressure to exacerbate cardiovascular risk. Sleep disruption is one of the most common symptoms of menopause, but whether it exacerbates the detrimental impact of menopause on cardiovascular health is not known. To address this knowledge gap, we propose to investigate the impact of sleep restriction on the cardiovascular phenotype in postmenopausal women and mice. The first aim of this study will assess the impact of estrogen loss and sleep restriction on blood pressure rhythms, examining how altered clock gene expression is associated with vascular dysfunction in both intact and ovariectomized female mice. The second aim will evaluate the effects of sleep restriction on blood pressure patterns and assess vascular clock gene and estrogen receptor expression in skeletal muscle biopsies using data from the SLEEP-IN study. We will employ state-of-the-art techniques, including radiotelemetry to monitor circadian rhythms of blood pressure and sleep architecture, droplet digital PCR, pulse wave velocity using high-resolution ultrasound, and biaxial pressure myography. Successful completion of this study will enhance our understanding of how sleep disruption influences cardiovascular pathogenesis post-menopause.

Dr. Zongbing You and his multidisciplinary research team including Drs. Rhea Bhargava, David Chae, Alun Wang, Yaozhong Liu, and Wenke Feng will conduct a pilot project entitled “Sex-based interactions between genes, hormones, and social factors in lupus” to investigate lupus pathogenesis. The Lupus Foundation of America estimates that 1.5 million Americans have a form of lupus including systemic lupus erythematosus (SLE). Ninety percent of lupus affects women of childbearing age. There is an 85% significantly increased risk of SLE among obese women compared to women with normal body mass index (BMI). Obesity has been considered as a major factor contributing to the onset and progression of SLE. However, the underlying mechanisms are not clear. This pilot project will test a hypothesis that obesity-associated inflammatory status exacerbates the functions of sex-based genes, hormones, environment, and social factors, to promote lupus pathogenesis. Three specific aims are proposed: Aim 1 will determine obesity and sex-based determinants in driving lupus pathogenesis in mice; Aim 2 will determine obesity and sex-based determinants in human lupus patients; and Aim 3 will determine obesity and sex-based social factors in human lupus patients. The new knowledge produced will guide precise medical management of lupus.

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects mainly women, but the disease severity is worse in males with an increased risk of developing lupus nephritis (LN). The cause of these differences remains unclear. Our recent investigations have shown differences in kidney and immune cell metabolism in SLE with and without nephritis. The epidemiology of kidney disease also differs by sex, with a greater risk of kidney failure in men. New data suggest that sex differences in proximal tubule metabolism may contribute to these differing outcomes. Changes in metabolic pathways not only support the biosynthetic and bioenergetic needs of a cell but also control the fate or function of immune cells. We have previously shown that metabolism of kidney cells in lupus can influence the proliferation of T cells in the kidney and hence influence the progression of lupus nephritis. B cells play an essential role in immune complex mediated disease like SLE and lupus nephritis. We have also demonstrated that changes in IgG glycosylation can lead to podocyte injury through metabolic reprogramming. In this proposal, we hypothesize that there is a link between altered metabolism in lupus and reprogramming of B cells eventually leading to aberrant IgG glycosylation and the development of lupus nephritis and this may contribute to the sex specific differences noted in SLE.

Click here to read Dr. Bhargava's Biography.