Sex Differences in Inflammation Across the Lifespan

项目总结 中风每年影响全球1500多万人，仍然是世界上导致残疾的主要原因。 美国。随着人口老龄化，中风的经济负担正在增加，这使得预防和治疗中风 血管疾病的治疗是一个关键的公共卫生问题。老年妇女患后遗症的可能性高出三分之一 卒中抑郁，卒中后认知功能减退率较高，卒中后生活质量较差 与年龄相仿的男性相比。造成这些差异的生物因素很多，包括社会因素， 细胞死亡和染色体性别的内在性别差异。作为新生儿，雄性老鼠(和男孩)更多 对缺血敏感。然而，随着年龄的增长，雌性小鼠(和女性)的结果会更差，部分原因是丢失 雌激素与生殖衰老的关系。我们发现X染色体上的逃逸基因 失活导致炎症反应的显著性别差异，无论是在脑内(小胶质细胞) 在外围地区。我们已经将我们的工作扩展到检查脂肪组织、肠道(和 其微生物群)，以及在脑血管系统中。我的研究重点是阐明 导致细胞死亡、炎症反应和神经修复的性别和年龄差异的机制 在整个生命周期中。我的计划的目标是将这些发现转化为新的、有针对性的疗法 男女患者均可使用。 在过去的20年里，我们的NINDS资助的研究计划进行了开创性的工作，改善了我们的 了解性行为如何导致细胞死亡。我们特别重视脑血管疾病， 并开发了调查新生儿损伤、血管性痴呆和中风的项目。我们的研究已经 研究表明，性别差异有助于对脑损伤的反应，并在多种疗效上 神经保护剂。越来越多的人认识到性是一个关键的生物变量，这导致了 NIH政策，现在要求将女性纳入临床前研究。性别差异也一直是 在临床环境中被确认。对这些因素的认识导致了临床试验的性别分化 结果和对导致妇女参加试验人数低的因素的更好的理解。在这 应用程序，我们将合并三个正在进行的NINDS资助的提案，重点是1。)与年龄相关的 炎症，2)染色体对中风的贡献，以及3.)社会孤立的有害影响。我们 将利用我们现有的知识来产生挑战现有范式的新研究 整合这些领域的信息。我们的研究方案将以我们过去的成功为基础，使用Cutting- EDGE神经生理学、免疫学和行为工具。成功完成这项研究将 增加我们对性行为在其他神经疾病中的理解。我的长期目标是最大化结果 适用于所有受神经系统疾病影响的患者。

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.