Sex Differences in Inflammation Across the Lifespan

项目摘要 中风每年影响全世界超过1500万人，并且仍然是世界上残疾的主要原因。 美国的随着人口老龄化，中风的经济负担正在增加，使得预防和 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- 中风后抑郁症患者，中风后认知能力下降的比率更高，中风后生活质量更差 与同龄男性相比。许多生物因素造成了这些差异，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，雄性小鼠（和男孩） 对缺血敏感。然而，随着年龄的增长，雌性小鼠（和女性）的结果更糟，部分原因是由于损失 雌激素与生殖衰老的关系我们发现X染色体上的基因 失活导致炎症反应的显著性别差异，无论是在大脑（小胶质细胞） 和外围。我们已经扩展了我们的工作，以检查脂肪组织，肠道（和 它的微生物组）和脑血管系统中。我的研究重点是阐明 细胞死亡、炎症反应和神经修复的性别和年龄差异机制 在整个生命周期中。我的项目的目标是将这些发现转化为新的靶向治疗方法， 用于男女患者。 在过去的20年里，我们的NINDS资助的研究计划开创了改善我们的工作， 了解性如何导致细胞死亡。我们特别重视脑血管疾病， 并开发了研究新生儿损伤、血管性痴呆和中风的项目。我们的研究 研究表明，性别差异有助于对脑损伤的反应，以及各种治疗的疗效。 神经保护剂越来越多的人认识到性别是一个重要的生物学变量， 国家卫生研究院的政策，该政策现在要求将女性纳入临床前研究。性别差异也是 在临床环境中识别。对这些因素的认识导致了临床试验的性别分解 结果和改善对导致试验中女性入组率低的因素的理解。在这 应用程序，我们将合并三个正在进行的NINDS资助的建议，重点是1。年龄相关 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，产生新的研究，挑战现有的范式， 整合这些领域的信息。我们的研究方案将建立在我们过去成功的基础上，使用切割- 神经生理学、免疫学和行为学的前沿工具。这项研究的成功完成将 增加我们对性在其他神经系统疾病中的理解。我的长期目标是最大化结果 所有神经系统疾病的患者。

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.