Sex Differences in Inflammation Across the Lifespan

一生中炎症的性别差异

• 批准号: 10665480
• 负责人: Louise D. McCullough
• 金额: $ 104.82万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665480
• 关键词: Adipose tissue; Affect; Age; Aging; Area; Behavioral; Biological; Biological Factors; Blood Vessels; Brain; Cell Death; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Clinical Trials; Disparity; Economic Burden; Elderly woman; Enrollment; Estrogens; Female; Funding; Funding Mechanisms; Genes; Goals; Immunologics; Inflammaging; Inflammation; Inflammatory Response; Ischemia; Knowledge; Longevity; Microglia; Mus; National Institute of Neurological Disorders and Stroke; Neurologist; Neuroprotective Agents; Outcome; Patients; Persons; Policies; Population; Prevention; Protocols documentation; Public Health; Quality of life; Research; Sex Differences; Social isolation; Stroke; Translating; United States; United States National Institutes of Health; Vascular Dementia; Vascular Diseases; Woman; Work; X Chromosome; age difference; boys; cardiovascular health; disability; genotypic sex; improved; innovation; male; men; microbiome; neonatal injury; neonate; nervous system disorder; neural repair; neurophysiology; novel; post stroke; post stroke cognitive impairment; post stroke depression; preclinical study; programs; reproductive senescence; response to brain injury; sex; social factors; success; targeted treatment; tool; translational scientist

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.

项目概要 中风每年影响全球超过 1500 万人，并且仍然是导致残疾的主要原因 美国。随着人口老龄化，中风的经济负担日益加重，使得中风的预防和 血管疾病的治疗是一个重要的公共卫生问题。老年女性患上老年痴呆症的可能性增加三分之一 中风抑郁、中风后认知能力下降的几率更高、中风后生活质量较差 与同龄男性相比。许多生物因素导致了这些差异，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）更容易 对缺血敏感。然而，随着衰老，雌性小鼠（和女性）的结果会更糟，部分原因是失去 雌激素与生殖衰老有关。我们发现X染色体上的基因逃逸 失活导致大脑（小胶质细胞）炎症反应的显着性别差异 和在外围。我们已将工作范围扩大到检查脂肪组织、肠道（以及 它的微生物组），以及脑血管系统。我的研究重点是阐明基本原理 细胞死亡、炎症反应和神经修复中性别和年龄差异的机制 整个生命周期。我的项目的目标是将这些发现转化为新颖的靶向疗法 适用于男女患者。 在过去的 20 年里，我们的 NINDS 资助的研究项目开创性的工作改善了我们的 了解性如何导致细胞死亡。我们特别重视脑血管疾病， 并制定了调查新生儿损伤、血管性痴呆和中风的计划。我们的研究有 研究表明，性别差异有助于对脑损伤的反应，以及多种药物的功效 神经保护剂。人们越来越认识到性别是一个重要的生物变量，这导致了 美国国立卫生研究院的政策，现在要求将女性纳入临床前研究。性别差异也已 在临床环境中确定。对这些因素的认识导致了临床试验的性别分类 成果以及对导致试验中女性入学率低的因素有了更好的了解。在这个 申请时，我们将整合三项正在进行的 NINDS 资助的提案，重点关注 1.) 与年龄相关的 炎症，2.) 染色体对中风的影响，以及 3.) 社会隔离的有害影响。我们 将利用我们现有的知识进行新的研究，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的成功基础上，使用切割- 边缘神经生理学、免疫学和行为工具。这项研究的成功完成将 增加我们对其他神经系统疾病中性的理解。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。