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Regulation of the transcription factor HLH-30/TFEB in aging

转录因子 HLH-30/TFEB 在衰老过程中的调控

基本信息

批准号：
9901412
负责人：
Louis Rene Lapierre
金额：
$ 32.27万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901412
关键词：
Address Affect Aging Autophagocytosis Biochemical Biological Assay Biological Markers Biological Models Caenorhabditis elegans Candidate Disease Gene Cell Culture System Cell Nucleus Cell physiology Cells Communication Data Development Disease Elements Enhancers Event Future Gene Expression Profiling Gene Silencing Genes Genetic Genetic Transcription Genomics Helix-Turn-Helix Motifs Human Intervention Intestines Knowledge Laboratories Link Longevity Mammalian Cell Mammals Mediating Metabolism Modeling Molecular Nature Nerve Degeneration Nuclear Nuclear Translocation Organism Orthologous Gene Pharmaceutical Preparations Pharmacology Phosphotransferases Play Positioning Attribute Post-Translational Protein Processing Process Proteins Proteomics Public Health RNA Interference RNA interference screen Recycling Regulation Reporting Research Role Signal Transduction Site Subcutaneous Tissue System Techniques Testing Therapeutic Tissues Transcriptional Regulation Translations Untranslated RNA age related chromatin immunoprecipitation design genetic approach genome-wide healthspan healthy aging innovation mutant new therapeutic target novel overexpression prevent therapy development tool transcription factor transcriptome transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Autophagy is a cellular recycling process with critical roles in aging and age-related diseases. Autophagy was originally described as a process mainly regulated at the post-translational level, but a role for transcriptional regulation has recently started to emerge. The relatively new concept of transcriptional regulation of the autophagy process provides an important new entry point toward developing therapies against age-related diseases. Recent studies in mammals have uncovered that the helix-loop-helix transcription factor EB (TFEB) is a central regulator of autophagy. We have reported that the C. elegans HLH-30 protein is a functional ortholog of TFEB and plays a broad role in C. elegans lifespan determination (Lapierre et al., Nature Communications, 2013). Specifically, we have found that HLH-30 is required for the lifespan extension observed in six independent longevity models, all of which are also known to be dependent on autophagy. Notably, HLH-30 is localized in the nucleus of intestinal cells in all of these long-lived mutants. Importantly, we have found TFEB to be similarly regulated in a mammalian longevity model suggesting that the longevity function of TFEB is also conserved. Therefore, we hypothesize that TFEB is a central player that modulates aging, at least in part by coordinating autophagic flux and, as such, represents an attractive longevity factor to molecularly understand in order to design approaches to promote healthspan and prevent aging. To address this hypothesis, we propose to use a combination of cutting-edge genetics and biochemical approaches to understand the spatial- and nuclear requirements for HLH-30 function in C. elegans lifespan (Aim 1); to address if downstream target genes besides those identified to function in autophagy are critical for longevity (Aim 2); and, finally, to identify genetic and pharmacological regulators of autophagy and HLH- 30/TFEB function (Aim 3). These studies are significant as they are the first to identify novel genetic regulators and post-translational modifications of HLH-30/TFEB in an unbiased fashion, and they will generate important information for future analysis of mammalian TFEB, a central regulator of autophagy as well as metabolism, in organismal aging. Furthermore, our studies are innovative because we employ C. elegans and mammalian cells in parallel to rapidly identify novel, conserved genes with roles in aging and to develop pharmacological solutions to enhance autophagy in order to prevent age-related diseases.

项目摘要/摘要自噬是一种细胞循环过程，在衰老和与年龄相关的疾病中起着关键作用。自噬是最初被描述为主要在翻译后水平上调节的过程，但在转录水平上监管最近开始浮出水面。转录调控的相对较新的概念自噬过程为开发针对年龄相关性疾病的治疗提供了一个重要的新切入点疾病。最近在哺乳动物中的研究发现，螺旋-环-螺旋转录因子EB(TFEB)是一种中枢自噬调节因子。我们已经报道了线虫HLH-30蛋白是TFEB的功能同源蛋白并在线虫寿命测定中发挥广泛作用(Lapierre等人，《自然通讯》，2013年)。具体来说，我们发现HLH-30是延长寿命所必需的，在六个独立长寿模型，所有这些模型也都已知依赖于自噬。值得注意的是，HLH-30的本地化版本所有这些长寿突变体的肠道细胞核。重要的是，我们发现TFEB也是如此在哺乳动物长寿模型中进行调节，表明TFEB的长寿功能也是保守的。因此，我们假设TFEB是调节衰老的中心参与者，至少部分是通过协调自噬通量，并因此代表了一个有吸引力的长寿因素，以分子理解，以便设计促进健康寿命和防止衰老的方法。为了解决这一假设，我们建议使用尖端遗传学和生化的组合了解线虫寿命中HLH-30功能的空间和核需求的方法 (目标1)；解决下游靶基因除了那些被发现具有自噬功能的基因外，是否对长寿(目标2)；最后，确定自噬和促黄体生成素的遗传和药理调节因素- 30/TFEB函数(目标3)。这些研究具有重要意义，因为它们是第一个发现新的基因调控因子和翻译后以公正的方式对HLH-30/TFEB进行修改，它们将为未来产生重要信息对哺乳动物TFEB的分析，TFEB是自噬和新陈代谢的中心调节器，在生物衰老中。此外，我们的研究具有创新性，因为我们同时使用线虫和哺乳动物细胞快速识别在衰老中起作用的新的、保守的基因，并开发药物解决方案加强自噬以预防与年龄有关的疾病。