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Novel longevity enhancing pathways regulated by mTOR

mTOR 调控的新长寿途径

基本信息

批准号：
10711017
负责人：
CHRISTIAN SELL
金额：
$ 38.51万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711017
关键词：
Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Animals Astrocytes Binding Brain Cell Aging Cell Compartmentation Cell physiology Cells Cellular Stress Chronic Clinical Cognition Collaborations Complex Cytoplasm Data Development Disease Elderly Evaluation Exposure to FRAP1 gene Family Fibroblasts Functional disorder Funding Gene Expression Profiling H19 RNA H19 gene Human In Situ Hybridization In Vitro Inflammation Intervention Knockout Mice Laboratories Link Longevity Maintenance Maps Mediator Metabolic MicroRNAs Modeling Mus Neurodegenerative Disorders Neurons Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Play Process Proteins RNA RNA-Protein Interaction Role Sampling Signal Transduction Sirolimus Somatic Cell TP53 gene Tissues Untranslated RNA Veronica Work adult stem cell age related aging brain brain tissue cell type experience improved inhibitor mTOR Inhibitor mTOR inhibition member mouse model novel pluripotency pre-clinical prevent response senescence side effect stem cell function stem cell population stem cells stressor symptomatology tau Proteins

项目摘要

Project Summary We have recently identified a novel link between the mTOR pathway and a specific long noncoding RNA, H19, which is critical during development and in adult stem cell populations. This work forms the basis for an ongoing R01 project. In this supplement, the central hypothesis is that mTOR inhibition by Rapa alleviates Alzheimer’s disease (AD) symptomatology by increasing the lncRNA H19. We find that levels of H19 decrease during senescence and differentiation, however Rapa increases H19 levels, prevents senescence, and maintains pluripotency. The results suggest that increasing H19 levels in response to mTOR inhibition may play a dual role, inhibiting senescence while simultaneously increasing pluripotency in adult stem cell populations. H19 is expressed at low levels in the brain and increased following some forms of damage, but little information exists regarding the function of H19 in the adult brain or in the context of AD. We have evidence that this axis is active in human astrocytes and we will explore the role of H19 in the CNS, first by evaluating the role of H19 during senescence of human astrocytes in response to stressors relevant to AD, second by evaluating the expression of H19 in mouse models of AD with and without rapamycin treatment, third by defining the specific binding partners of H19 in astrocytes and neurons.

项目摘要我们最近发现了mTOR通路和一个特定的长非编码RNA之间的新联系， H19，在发育和成体干细胞群中至关重要。这项工作的基础是正在进行的R01项目。在这篇补充文章中，中心假设是拉帕对mTOR的抑制作用，通过增加lncRNA H19来降低阿尔茨海默病（AD）的发病率。我们发现H19的水平在衰老和分化过程中下降，而Rapa增加H19的水平，水平，防止衰老，并保持多能性。结果表明，增加H19水平，对mTOR抑制的反应可能起双重作用，抑制衰老，同时增加成体干细胞群的多能性。H19在脑中以低水平表达，并且在脑中以高水平表达。在某些形式的损伤之后，但关于H19在成人大脑中的功能的信息很少或者在AD的上下文中。我们有证据表明这个轴在人类星形胶质细胞中是活跃的，我们将探索 H19在CNS中的作用，首先通过评估H19在人星形胶质细胞衰老过程中的作用，第二，通过评估H19在AD小鼠模型中的表达，有和没有雷帕霉素治疗，第三，通过定义星形胶质细胞中H19的特异性结合伴侣，和神经元。