Sex Differences in Inflammation Across the Lifespan

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PROJECT SUMMARY Stroke affects over 15 million people worldwide each year and remains the leading cause of disability in the United States. The economic burden of stroke is increasing as the population ages, making the prevention and treatment of vascular disease a critical public health issue. Elderly women are a third more likely to develop post- stroke depression, have greater rates of post-stroke cognitive decline, and have poorer quality of life after stroke compared to age-matched men. Many biological factors contribute to these disparities, including social factors, intrinsic sex differences in cell death, and chromosomal sex. As neonates, male mice (and boys) are more sensitive to ischemia. However, with aging, female mice (and women) have worse outcomes, in part due to loss of estrogen with reproductive senescence. We have found that genes on the X chromosome that escape inactivation contribute to significant sex differences in the inflammatory response, both in the brain (microglia) and in the periphery. We have extended our work to examine sex differences in adipose tissue, in the gut (and its microbiome), and in the cerebral vasculature. My research focuses on elucidating the fundamental mechanisms responsible for sex and age differences in cell death, inflammatory responses, and neural repair throughout the lifespan. The goal of my program is to translate these findings into novel, targeted therapies for use in patients of both sexes. Over the past 20 years, our NINDS-funded research program has pioneered work that has improved our understanding of how sex contributes to cell death. We have a particular emphasis on cerebrovascular diseases, and have developed programs investigating neonatal injury, vascular dementia, and stroke. Our studies have revealed that sex differences contribute to the response to brain injury, and in the efficacy of a variety of neuroprotective agents. The growing recognition that sex is a critical biological variable has led to changes in NIH policy, which now mandates inclusion of females in pre-clinical studies. Sex differences have also been identified in the clinical setting. Recognition of these factors has led to sex disaggregation of clinical trial outcomes and an improved understanding of factors that contribute to low enrollment of women in trials. In this application, we will consolidate three ongoing NINDS-funded proposals that focus on 1.) age-related inflammation, 2.) the chromosomal contribution to stroke, and 3.) the detrimental effects of social isolation. We will leverage our existing knowledge to produce new research that challenges the existing paradigm by integrating information across these areas. Our research protocol will build on our past successes using cutting- edge neurophysiological, immunological, and behavioral tools. Successful completion of this research will increase our understanding of sex in other neurological disorders. My long-term goal is to maximize outcomes for all patients affected by neurological disease.