Longevity and Stress Resistance

长寿和抗压能力

• 批准号: 7186117
• 负责人: STEPHEN F VATNER
• 金额: $ 182.23万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186117
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adenylate Cyclase; Adolescent; Adverse effects; Advisory Committees; Affect; Age; Age Factors; Age-Months; Aging; Aging-Related Process; Allegra; Animal Disease Models; Animal Housing; Animal Model; Animals; Antioxidants; Apoptosis; Apoptotic; Applications Grants; Appointment; Arts; Back; Biochemical; Biochemistry; Bioinformatics; Biological; Biometry; Blood Circulation; Bone Development; Boxing; Breeding; Brothers; Calcium; Caloric Restriction; Carbon Dioxide; Cardiac; Cardiac Myocytes; Cardiology; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cell Separation; Cell Size; Cell Survival; Cell physiology; Cells; Cellular biology; Centrifugation; Chicago; Chronic; Class; Collaborations; Collagen; Color; Commit; Communities; Complex; Computational Technique; Computer Systems; Computer software; Computers; Critiques; Cyclic AMP-Dependent Protein Kinases; DNA; Data; Data Analyses; Databases; Deacetylation; Dentistry; Depth; Discipline; Disease model; Disruption; Doctor of Medicine; Doctor of Philosophy; Dry Ice; Electronics; End Point; Engineering; Ensure; Environment; Enzymes; Equipment; Exhibits; Family; Family suidae; Feedback; Fluorescent Probes; Fostering; Functional disorder; Funding; Gamma counter; Gene Silencing; Genes; Genetic; Genetic Crosses; Genetically Engineered Mouse; Genome; Genomics; Genotype; Goals; Grant; Heart; Histone Deacetylase; Histopathology; Homologous Gene; Hormones; Human; Hypertrophy; Ice; Illinois; Image; Image Analysis; Immunity; In Vitro; Incubators; Individual; Inflammation; Institutes; Institution; Insulin Receptor; Insulin-Like Growth Factor I; Interdisciplinary Study; Internal Medicine; Internet; Intervention; Ischemia; Joints; Journals; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Laboratories; Laboratory Animal Production and Facilities; Lasers; Leadership; Lesion; Letters; Life; Link; Liquid substance; Liver; Longevity; Lower Organism; MEKs; Magnetic Resonance Imaging; Malignant Neoplasms; Mammals; Manganese Superoxide Dismutase; Mass Spectrum Analysis; Measurement; Mediating; Medical; Medicine; Mentors; Metabolic; Metabolic Pathway; Metabolism; Microbiology; Microscope; Mission; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Biology; Molecular Genetics; Molecular Medicine; Mus; Myocardial; Myocardial Ischemia; Myocardium; Names; Natural History; Neoplasms; New Jersey; Nitrogen; Numbers; Operating Rooms; Operative Surgical Procedures; Oranges; Organism; Osteoporosis; Oxidative Stress; Participant; Pathologic; Pathology; Pathway interactions; Pharmacology; Phenotype; Physiological; Physiological reperfusion; Physiology; Play; Polymerase Chain Reaction; Preparation; Primates; Principal Investigator; Process; Production; Program Research Project Grants; Protein Isoforms; Protein Overexpression; Proteomics; Psychiatry; Public Health; Publications; Quarantine; Rapid Access to Intervention Development; Rate; Reactive Oxygen Species; Recording of previous events; Recovery Room; Reperfusion Therapy; Reporting; Research; Research Institute; Research Personnel; Resistance; Resolution; Resource Sharing; Resources; Role; Role playing therapy; Safety; Science; Signal Pathway; Signal Transduction; Site; Slide; Somatotropin; Spleen; Stainless Steel; Stimulus; Stress; Study Section; Superoxide Dismutase; Support of Research; Sus scrofa; System; Techniques; Technology; Telefacsimile; Telephone; Temperature; Testing; Thymus Gland; Training; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Universities; Veterinarians; Walking; Water; Water Purification; Women' s Health; Wood material; Work; Yeasts; adenylyl cyclase type V; age effect; aging population; animal care; anti aging; anticancer research; base; beta counter; bone; catalase; comparative; computerized; data space; dietary restriction; digital; disability; experience; fluorescence microscope; fly; foot; hemodynamics; human PEN-2 protein; human SOD2 protein; ileum; in vivo; insight; insulin signaling; interest; laboratory facility; medical schools; member; mouse model; multidisciplinary; muscle metabolism; novel; pediatric department; posters; pressure; prevent; professor; programs; protective effect; repaired; response; senescence; skills; statistics; success; symposium; tissue/cell culture; tumor; yeast genetics; young adult

DESCRIPTION (provided by applicant): The overall theme of this project is to test the hypothesis that life span extension, longevity and stress resistance are mediated by common mechanisms. Growing lines of evidence suggest that the longevity of a wide variety of organisms, from yeast to worms and flies to mammals, is regulated by defined molecular mechanisms, including Sir2, an NAD-dependent histone deacetylase, and the adenylyl cyclase-protein kinase A pathway. A major limitation to understanding the key regulatory mechanisms responsible for causing the adverse effects of aging, or conversely, those that extend longevity, is the lack of animal models which exhibit prolonged lifespan and which do not develop cardiomyopathy or osteoporosis or other end- points, which are normally observed with aging. The model, which is accepted best for increasing longevity from yeast to primates, is caloric restriction. Relatively few other models for longevity are available. In this connection, we have recently identified a novel, genetically engineered animal model, which lives longer than wild type animals and does not exhibit many of the cardiac and osteoporotic features of old age, i.e., mice with the adenylyl cyclase (AC) type 5 "knocked out" (ACS KO). It is our contention that examining mechanisms that are unique to the ACS KO model will provide important insight into the aging process and, potentially, mechanisms which might be utilized to reverse this process. Projects 1 and 2 examine these mechanisms in this mouse model. In addition, Project 3 has developed and will study other mouse models of aging and stress resistance, related to Sir2alpha. The central hypothesis in that project is that Sir2alpha mediates anti-aging as well as cell protective effects in the heart in vivo. These 3 projects are supported by 5 cores: Administration/Physiology; Animal Care; Genomics/Proteomics; Bioinformatics/Biostatistics; Pathology. This Program Project has major implications for public health. The disability associated with aging has a major impact on the public health and the U.S. economy. Finding molecular switches, such as the ones described in this project, could ameliorate disability with aging and would be a major step forward.

描述（由申请人提供）：该项目的总体主题是检验寿命延长、长寿和抗逆性是由共同机制介导的假设。越来越多的证据表明，从酵母到蠕虫，从苍蝇到哺乳动物，各种生物的寿命都受到确定的分子机制的调节，包括Sir2，一种nad依赖性组蛋白去乙酰化酶，以及腺苷酸环化酶-蛋白激酶a途径。了解导致衰老或相反延长寿命的不良影响的关键调控机制的主要限制是缺乏表现出延长寿命且不发展为心肌病或骨质疏松症或其他终点的动物模型，而这些通常是随着衰老而观察到的。从酵母菌到灵长类动物，人们普遍接受的延长寿命的最佳模式是热量限制。相对较少的其他寿命模型可用。在这方面，我们最近确定了一种新的基因工程动物模型，它比野生型动物寿命更长，并且没有表现出老年的许多心脏和骨质疏松症特征，即具有5型腺苷酸环化酶（AC）的小鼠“敲除”（ACS KO）。我们的观点是，研究ACS KO模型特有的机制将为衰老过程提供重要的见解，并可能用于逆转这一过程的机制。项目1和项目2在小鼠模型中检验这些机制。此外，Project 3已经开发并将研究与Sir2alpha相关的其他小鼠衰老和抗逆性模型。该项目的中心假设是Sir2alpha在体内具有抗衰老和保护心脏细胞的作用。这3个项目由5个核心支持：管理/生理学；动物保健;基因组学和蛋白质组学;生物信息学/生物统计学;病理。该方案项目对公共卫生具有重大影响。与老龄化相关的残疾对公众健康和美国经济产生了重大影响。找到分子开关，比如在这个项目中描述的那些，可以改善衰老带来的残疾，这将是向前迈出的重要一步。