Selective vulnerability of cell types in brain aging and Alzheimer's disease

大脑衰老和阿尔茨海默病中细胞类型的选择性脆弱性

• 批准号: 10730037
• 负责人: Doudou Yu
• 金额: $ 4.92万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-09-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730037
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Apolipoprotein E; Autopsy; Biology of Aging; Body Composition; Body Weight; Brain; Brain region; Cell Nucleus; Cells; Circadian Dysregulation; Circadian Rhythms; Cognition; Complex; Computational Biology; Country; Cues; Data; Development; Diet; Disease; Disease Progression; Eating; Epigenetic Process; Equilibrium; Exhibits; Female; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health; Heterochromatin; Heterogeneity; Hormones; Human; Hypothalamic structure; Immune; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Intrinsic factor; Knowledge; Laboratories; Link; Longevity; Machine Learning; Mammals; Metabolism; Methods; Microglia; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Neurosecretory Systems; Outcome; Phase; Phenotype; Physiological; Postdoctoral Fellow; Predisposition; Process; Publishing; Regulation; Research Project Grants; Resolution; Sex Differences; Sleep; Stress; Testing; Tissues; Training; Universities; Up-Regulation; Woman; Work; X Inactivation; aged; aging brain; biological adaptation to stress; cell age; cell type; functional decline; genotypic sex; healthspan; healthy aging; in vivo; insight; machine learning method; machine learning model; male; men; mouse model; neural; normal aging; novel marker; preservation; resilience; response; sex; sexual dimorphism; sleep regulation; specific biomarkers; tool; transcriptomics

Project Summary Major hallmarks of aging and neurodegeneration include cognitive decline, altered body composition, dysregulation of circadian rhythms, and changes in neuroendocrine systems. The hypothalamus is the brain region that harbors a diversity of neuronal subtypes that coordinate these important functions. Yet, the extent to which changes in the hypothalamus underlie functional decline in normal aging and neurodegeneration is not well understood. Intriguingly, interventions targeting the hypothalamus can significantly extend lifespan in mice, with a discrepancy in females versus males. Moreover, alterations in sleep and body weight can occur prior to the onset of neurodegeneration, for example in Alzheimer’s Disease (AD). One challenge in understanding the aging process is that it is highly heterogeneous, meaning that different cell-types age differently. For example, in brain aging, within individuals, the immune cells (microglia) age very differently from neurons. Moreover, across individuals, women are more susceptible to age-associated neurodegenerative diseases such as Alzheimer’s disease (AD) than men. However, the selective vulnerability of different cell-types in the brain in aging and AD, and the cell-type specific mechanism underlying female bias in brain aging are largely unknown. For the F99 phase of this proposal, in Dr. Webb’s laboratory at Brown University, I will build on my foundational work in which I defined the cell-type transcriptional changes that occur in the aging female mouse hypothalamus. I will perform machine learning analysis to identify signatures of cell vulnerability and resilience with age and extend this work to a model of neurodegeneration (AD mouse models and human post-mortem tissue). Understanding the selective vulnerability in aging and AD can help develop precise interventions to specifically target the vulnerable neurons to slow down brain aging and promote health span. For the K00 phase of this proposal, I will seek to understand the epigenetic mechanisms regulating sex-differences in brain aging. My previous analysis found increased expression of Xist, the master regulator for silencing one of the two chrX in females in eutherian mammals, in aging and AD brain. Given that chrX is enriched for neural and immune genes and the known loss of heterochromatin in aging, I hypothesize that Xist is required for maintaining chrX silencing to protect neurons in brain aging. I will test this hypothesis by epigenetically activating or silencing Xist in induced neurons derived from aged fibroblasts to determine the impact on neuronal aging, and in vivo to reveal the cell-type specific response to the chrX-specific perturbation. This work will contribute to the understanding of the heterogeneity, especially cell-type specific and sex-specific vulnerability, in normal brain aging and AD. Further, it will lead to the discovery of novel biomarkers to assess age and AD status at single cell resolution, which will contribute to the development of cell-type specific interventions. To successfully complete these goals, I will gain extensive training from a team of experts in computational biology, biology of aging, neurodegeneration, and neuroscience.

项目摘要 衰老和神经退行性的主要标志包括认知能力下降，身体成分改变， 昼夜节律的失调和神经内分泌系统的变化。 携带着各种神经元亚型的区域，以协调这些重要功能。 正常衰老和神经退行性的正常衰老的功能下降基础下降的变化不是 很有趣的是。 此外 神经变性的发作，例如阿尔茨海默氏病（AD）。 衰老过程是它高度高度的热量。 在个体内，免疫细胞（小胶质细胞）与神经元的年龄差异很大。 在整个个人中，女性更容易受到年龄增长的神经退行性疾病的影响 但是，阿尔茨海默氏病（AD）比男性。 衰老和AD，以及脑衰老中女性偏见的细胞类型特异性机制是未知的。 对于本提案的F99阶段，在韦伯博士的布朗大学实验室中，我将建立Onmy 我定义了衰老雌鼠老鼠老鼠的细胞类型转录变化的基础工作 下丘脑。 随着年龄的增长并将这项工作扩展到神经变性的模型（AD鼠标模型和人类验尸 组织）。 特别针对脆弱的神经元，以减慢大脑衰老并促进健康跨度。 对于该提案的K00阶段，我将Seeek了解调节的表观遗传机制 大脑衰老的性别差异。 在衰老和AD大脑中，在Eutherian Mamals中的女性中，将两个Chrx之一沉默。 富含神经和免疫ANES和衰老中异染色质的已知丧失，我假设XIST 维持CHRX沉默以保护脑衰老中的神经元所必需。 从老年成纤维细胞中的诱导神经元中表观遗传激活或沉默的XIST，以确定您 对神经元衰老的影响和体内对CHRX特异性扰动的特异性反应的影响。 这项工作将有助于理解异质性，尤其是细胞类型的特定和 性别特定的脆弱性，在正常的大脑衰老和AD中。 评估单细胞分辨率下的年龄和广告状态，这将有助于细胞类型的发展 具体的干预措施。 计算生物学，衰老，神经退行性和神经科学的专家。