The developmental effects of sex chromosomes and hormones specify microglial inflammation in Alzheimer's diseaes

性染色体和激素的发育影响明确了阿尔茨海默病中的小胶质细胞炎症

• 批准号: 10370098
• 负责人: ERIN G REED
• 金额: $ 39万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370098
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Biochemical; Biological Factors; Biology; Brain; Cell Differentiation process; Cells; Complement; Dementia; Deposition; Development; Developmental Process; Disease; Disease Outcome; Disease Progression; Estradiol; Feminization; Four Core Genotypes; Gene Expression; Genetic; Germ Cells; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Immune; Incidence; Indomethacin; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Longevity; Masculine; Measures; Mediating; Mediator of activation protein; Methodology; Methods; Microglia; Mission; Modeling; Molecular; Morphology; Mus; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Receptors; Onset of illness; Outcome; PTPRC gene; Play; Prevalence; Prevention; Prevention strategy; Probability; Process; Proteins; Public Health; Research; Role; Severity of illness; Sex Chromosomes; Sex Differences; Signal Transduction; Specific qualifier value; Techniques; Testing; United States National Institutes of Health; Woman; age related; base; brain cell; combat; extracellular; immune activation; inflammatory milieu; innovation; insight; mouse model; neurochemistry; neurofilament; neuroinflammation; novel; novel therapeutic intervention; receptor function; reduce symptoms; sex; sexual dimorphism; success; therapeutically effective; therapy development; treatment strategy

PROJECT SUMMARY/ABSTRACT Although women are known to be disproportionally affected by Alzheimer’s disease (AD), the underlying biology for this difference is unresolved. Our long-term goal is to help develop therapies that can be used in the prevention and treatment of Alzheimer’s disease and other dementias where inflammation plays a critical role. The overall objectives in this application are to (i) define the mechanisms that specify the inflammatory response in the AD brain, and (ii) elucidate whether these are altered in the presence of circulating hormones. Our central hypothesis is that sex differences in the brain’s immune cells are driven by sex chromosomes and gonadal steroid hormones, resulting in divergent inflammatory processes and therefore AD onset and progression. The rationale for this project is that determining how genetic and hormonal mediators contribute to sex differences in the neuroinflammatory processes in AD will provide a strong scientific framework whereby new therapeutic strategies can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the contribution of sex chromosomes to the inflammatory environment of the AD brain; and 2) Determine the organizational effects of sex hormones in establishing the inflammatory response in the AD brain. Under the first aim, the 5xFAD mouse model of AD will be combined with the Four Core Genotype (FCG) mouse to separate chromosomal and gonadal sex in the context of AD. Inflammation will be assessed using biochemical and molecular techniques to examine immune cell activation and neuronal health and survival. For the second aim, the brains of 5xFAD mice will be masculinized or feminized neonatally to ascertain the effects of gonadal hormones on inflammatory processes. The innovation of this project lies in: 1) the aspects of sex not previously considered in AD models, 2) the contribution of cell differentiation during development to AD risk in ways not previously considered, and 3) the use of methodologies to shift the disease paradigm away from protein functional differences towards expression differences. Providing critical insights to the mechanisms giving rise to immune dysregulation and neuroinflammation in AD are significant because they have the potential to become the basis for new therapeutic strategies.

项目摘要/摘要 尽管众所周知，女性受阿尔茨海默氏病（AD）的影响不成比例 这种差异的基本生物学尚未解决。我们的长期目标是帮助开发可以成为的疗法 用于预防和治疗阿尔茨海默氏病和其他痴呆症，其中炎症起作用 关键作用。本应用程序中的总体目标是（i）定义指定的机制 AD大脑中的炎症反应，（ii）阐明它们是否在存在下改变 循环激素。我们的中心假设是，大脑免疫细胞中的性别差异是由 性染色体和性腺立体恐怖片，导致炎症过程不同，因此 广告发作和进展。该项目的理由是确定遗传和马匹如何 介体在AD中的神经炎症过程中的性别差异做出了贡献 可以开发新的治疗策略的科学框架。中心假设将是 通过追求两个具体目的测试：1）确定性染色体对炎症的贡献 广告大脑的环境； 2）确定性激素在建立的组织效应 广告大脑中的炎症反应。在第一个目标下，AD的5xFAD鼠标模型将合并 在AD的背景下，使用四种核心基因型（FCG）小鼠分离染色体和性腺性别。 炎症将使用生化和分子技术评估以检查免疫细胞激活 以及神经元健康和生存。对于第二个目标，5xfad小鼠的大脑将被男性化或 通过新生儿进行女性化，以确定性腺恐怖对炎症过程的影响。创新 该项目的内容在于：1）性别以前在AD模型中未考虑的性方面，2）细胞的贡献 开发过程中以先前未考虑的方式与广告风险的区分，3）使用 将疾病范式从蛋白质功能差异转移到表达的方法 差异。为导致免疫失调的机制提供关键见解和 AD中的神经炎症很重要，因为它们有可能成为新的基础 治疗策略。