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Nutrient Sensing, Hematopoietic Stem Cell Metabolism and Aging

营养感应、造血干细胞代谢和衰老

基本信息

批准号：
10447806
负责人：
DANICA CHEN
金额：
$ 39.25万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447806
关键词：
Acetyl Coenzyme A Acetylation Address Adult Age Aging Animals Antioxidants Blood Bone marrow failure Caloric Restriction Cell Aging Cell Maintenance Cell physiology Cells Cellular Metabolic Process Citric Acid Cycle Deacetylase Defect Deterioration Development Dietary Intervention Disease Enzymes Event Gene Expression Profiling Genetic Genomic approach Hand Hematopoietic Hematopoietic Stem Cell Research Hematopoietic System Hematopoietic stem cells Homeostasis Incidence Knockout Mice Lead Life Link Longevity Maintenance Mammals Maps Membrane Potentials Metabolic Metabolism Mitochondria Mitochondrial Proteins Molecular Molecular Profiling Molecular Target Myeloid Leukemia Nutrient Oxidative Stress Physiological Positioning Attribute Process Production Reactive Oxygen Species Regenerative capacity Regimen Regulation Role SOD2 gene Signal Transduction Solid Stress System Testing Therapeutic Tissues Transgenic Organisms Up-Regulation Work age related aged detection of nutrient dietary drug development fatty acid oxidation functional decline gain of function hematopoietic stem cell aging hematopoietic stem cell fate human old age (65+)improved improved functioning injury and repair insight leukemia loss of function mitochondrial membrane mitochondrial metabolism mouse model novel oxidative damage prevent programs protein folding response self-renewal senescence sensor stem cell function tool

项目摘要

Project Summary The maintenance of the hematopoietic system throughout adult life relies on the persistence of hematopoietic stem cells (HSCs). With age, the ability of HSCs to self- renew declines and the differentiation potential of HSCs is dysregulated. HSC aging is thought to be a major cause of compromised maintenance of the hematopoietic system in the aged animals. Understanding the molecular mechanisms underlying HSC aging holds the promise to identify novel molecular targets to ameliorate age-related deterioration in HSCs and to prevent bone marrow failure. Calorie restriction (CR), a dietary regimen known to extend lifespan across species, greatly prevents hematopoietic senescence, improves HSC function, and suppresses myeloid leukemia development. We propose to use CR as a platform to search for genetic regulators that modulate HSC aging and diseases of HSC origin. We have established a CR mouse model to study the effects of nutrient on HSC aging. Using the established system, we will elucidate the nutrient sensors and their downstream signaling events that relay the nutrient signals to maintain mitochondrial metabolic homeostasis and regulate HSC fate choices. We will also determine how this process is dysregulated during the aging process. This application is significant because it addresses outstanding questions of the SHINE program: 1) What are the regulatory factors governing aged HSC fate choices? 2) Are HSC-intrinsic changes coordinated with extrinsic signals during aging? 3) How do HSC metabolic processes change with age? 4) Can these HSC metabolic processes be modified to rejuvenate the blood system?

项目摘要造血系统在整个成年生活中的维持依赖于造血干细胞（HSC）的持续存在。随着年龄的增长，HSC自我调节的能力再生能力下降，HSC的分化潜能失调。HSC老化是被认为是造血系统维持受损的主要原因在老年动物理解HSC衰老的分子机制有望发现新的分子靶点，以改善年龄相关的造血干细胞的退化和防止骨髓衰竭。热量限制（CR），a 已知的延长物种寿命的饮食方案，极大地阻止了造血衰老，改善HSC功能，并抑制骨髓性白血病的发展。我们建议使用CR作为一个平台来寻找调节HSC的遗传调节因子衰老和HSC起源的疾病。我们建立了CR小鼠模型来研究营养素对HSC老化的影响。利用建立的系统，我们将阐明营养传感器及其下游信号传导事件，其传递营养信号以维持线粒体代谢稳态和调节HSC命运选择。我们还将确定这是如何在衰老过程中，这一过程失调。这一应用具有重要意义，因为它解决了SHINE计划中悬而未决的问题：1）监管是什么决定老年HSC命运选择的因素？2)HSC-内在变化是否协调与外界信号的联系3)HSC代谢过程如何随着年龄？4)这些HSC的代谢过程是否可以被修改以使血液恢复活力系统中？