LIFESPAN AND MECHANISMS OF STRESS RESISTANCE IN GH/IGF MUTANTS

GH/IGF 突变体的寿命和抗应激机制

• 批准号: 8448205
• 负责人: RICHARD A MILLER
• 金额: $ 34.88万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448205
• 关键词: Address; Adipocytes; Adipose tissue; Age; Aging; Aging-Related Process; Animals; Apoptotic; Autopsy; Biochemical; Biological Markers; Biology of Aging; Cadmium; Cataract; Cell Line; Cell membrane; Cells; Cellular Stress; Characteristics; Collaborations; Data; Dermal; Disease Resistance; Dose; Elderly; Endocrine; Epigenetic Process; Equilibrium; Evaluation; Exposure to; Family; Fibroblasts; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Goals; Health; Heat shock proteins; Heterozygote; Hormones; Housing; Hydrogen Peroxide; Hypersensitivity skin testing; Immune; In Vitro; Instruction; Insulin-Like Growth Factor I; Investigation; Lead; Learning; Lesion; Life; Light; Link; Liver; Living Donors; Longevity; Measures; Messenger RNA; Metabolic; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Mouse Cell Line; Mus; Muscle; Mutant Strains Mice; Organ; Oxidation-Reduction; Oxidative Stress; Paraquat; Pathology; Pathway interactions; Pattern; Periodicity; Peroxides; Phosphotransferases; Preventive Medicine; Property; Proteins; Regulation; Research; Resistance; Resistance profile; Resources; Rotenone; Severities; Signal Transduction; Skeletal Muscle; Skin; Stress; System; T-Lymphocyte Subsets; Testing; Thapsigargin; Tissues; Tunicamycin; anti aging; base; cell type; end of life; human FRAP1 protein; human GHR protein; in vitro testing; in vivo; indexing; inhibitor/antagonist; juvenile animal; mature animal; middle age; mouse model; mutant; peripheral blood; programs; repaired; response; sex; trait; ultraviolet irradiation; young adult

PROJECT 3 focuses on the idea that diminished exposure to GH and/or IGF-1 signals in early life leads both to lifespan extension and to a spectrum of cellular abnormalities that we have documented in fibroblasts from long-lived Snell dwarf mutant mice, including sensitivity to inducers of ER stress, resistance to a broad range of lethal agents, and resistance to inhibition of the plasma membrane redox system (PMRS). Eight varieties of mice will be compared in the project, including: (a) Snell dwarf mice; (b) LID mice that lack IGF-1 expression in liver; (c) IGF-1 midi mice, with abnormally low levels of IGF-1 and high GH levels; (d) IGF-1 R het mice, with abnormally low response to IGF-1, (e) GHRKO mice, which lack GH receptors in all tissues; and (f) three new varieties of tissue-specific GHR mutants, which lack GH receptors, respectively, in liver, adipose tissue, or skeletal muscle. Aim 1will test skin-derived fibroblast cell lines from these mice, evaluating resistance to lethal oxidative and non-oxidative stresses (peroxide, paraquat, cadmium, and UV), to which Snell dwarf cells are resistant, and inducers of the unfolded protein response (tunicamycin, thapsigargin), to which Snell cells are sensitive. PMRS reactivity will be tested using non-lethal doses of rotenone. Fibroblasts from week-old mice will be tested to see if stress patterns require post-natal maturation, and from middle-aged mice to see if the stress-resistance profile lasts into midlife. Pre- adipocytes will be tested to see if they, too, show stress resistance when taken from long-lived donor stocks. Aim 2, using biochemical approaches, will test in vitro fibrobtasts, and tissues from intact and UV-exposed mice, for four pathways involved in stress resistance: Erk-family MAP kinase signals, activation of mTOR, repair and apoptotic pathways of the unfolded protein response, and mRNA levels for heat shock proteins and HSFs. Aim 3 will measure lifespan in the three tissue-specific GHRKO models, and will measure three age-sensitive traits (immune status, cataracts, and activity) as indices of delayed aging. Project 3 will provide resources to other parts of the program: tissues from terminal necropsies to Core B, fibroblast lysates for gene expression analyses to Project 1, and adipose tissue depots to Project 4. Project 3 will provide tests of the hypothesis that endocrine manipulations that modulate stress resistance lead to extended longevity, and in collaboration with the program as a whole will shed new light on the connections linking cellular stress resistance to genetic and pharmacologic modulators of endocrine and adipose tissues. RELEVANCE (See instructions): This project is intended to suggest clues about the biology of aging and late-life illness, provide models for investigation of the aging process, and confirm or refute ideas about proposed anti-aging drugs. Positive findings could, potentially, suggest new strategies in preventive medicine.

项目3的重点是在生命早期减少GH和/或IGF-1信号的暴露会导致这两种情况