Role of S6 Kinase 2 in Aging

S6 激酶 2 在衰老中的作用

• 批准号: 8700900
• 负责人: Remi-Martin Laberge
• 金额: $ 10万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700900
• 关键词: Adverse effects; Age; Age-Months; Aging; Animal Model; Animals; Apoptosis; Apoptotic; Atrophic; Autopsy; Award; Biochemical; Bioinformatics; Biological; Blood; Cardiovascular Diseases; Cataract; Cell Aging; Cell secretion; Cells; Characteristics; Chronic; Cognitive; Collaborations; Complex; DNA Damage; Data; Disease; Down-Regulation; Failure; Female; Fibroblasts; Genes; Goals; Health; Health Benefit; Histology; Human; Impaired cognition; Inflammation; Inflammatory; Institutes; Intervention; Knowledge; Lesion; Link; Longevity; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mentors; Mus; Nerve Degeneration; Nuclear; Oncogenic; Organism; Pathology; Pathway interactions; Pharmacologic Substance; Phase; Phenotype; Phosphotransferases; Physiology; Preparation; Production; Proteins; RNA Interference; Regulation; Research; Research Proposals; Ribosomal Protein S6 Kinase; Role; Sirolimus; Stress; Substrate Specificity; Techniques; Testing; Tissues; Translating; Tumor Suppressor Proteins; Tumor Tissue; Wild Type Mouse; Work; age related; animal tissue; arm; career; cell growth; chemotherapeutic agent; chemotherapy; clinical application; cytokine; detection of nutrient; end of life; experience; human FRAP1 protein; improved; in vivo; insight; mTOR protein; male; man; mouse model; novel; professor; programs; public health relevance; response; ribosomal protein S6 kinase, 70kD, polypeptide 2; senescence; skills; small hairpin RNA; tumor

DESCRIPTION (provided by applicant): Modulation of the nutrient sensing pathway governed by the protein TOR (target of rapamycin) leads to lifespan extension in various organisms. This discovery has outstanding potential health benefits for humans. However, failure to understand its mechanisms of action has slowed down its application for clinical healthspan benefits. The mammalian TOR complex 1 (mTORC1) can be pharmacologically inhibited with the compound rapamycin. Rapamycin inhibits a particular subset of TOR activity, mainly through S6 Kinase 1 and 2 (S6K1 and S6K2). Rapamycin extends lifespan of male and female mice, but also has negative effect on health via unknown mechanisms. S6K1-deficient female mice, but not male mice, have an extended lifespan suggesting a role for the other kinase, S6K2, in the lifespan extension by rapamycin. Also, no data is available regarding the lifespan of S6K2-deficient mice. Interestingly, S6K2 has been link to protect cells against apoptosis. Another, tumor suppressor mechanism is cellular senescence (a permanent cell growth arrest program). It is possible that cells expressing S6K2 favor senescence rather than apoptosis as a mechanism to protect against tumor apparition. Cellular senescence accumulation with age is widely seen as a contributor of aging phenotypes. These cells secrete proinflammatory cytokines a phenotype termed SASP for senescence- associated secretory phenotype and, therefore, their accumulation in an aging organism could contribute to chronic inflammation known to stimulate the apparition of age-related pathologies. Recently, it was shown that clearance of senescent cells alleviates age-related phenotypes in the progeroid mouse model. My preliminary data show that, in senescent cells in culture, rapamycin decreases the production of these proinflammatory cytokines and that similar results are obtained by downregulating S6K2, but not S6K1. My hypothesis is that reduction of S6K2 activity extends health- and lifespan by alleviating the senescent phenotype in aging mice. My research proposal will test the hypothesis that dampening complex activity by rapamycin or other means decreases the SASP, particularly its pro-inflammatory arm, by suppressing S6K2 activity. I will further test the hypothesis that suppression of S6K2 activity results in extension of both lifespan and healthspan in mice. Further, I will explore the mechanisms by which S6K2 acts and identify its major substrates. I will accomplish these aims by evaluating cells, tissues phenotypes and the physiology of S6K2 deficient cells and mice, as well as S6K2-expressing or -depleted human fibroblasts. I will examine the cells, tissues and animals for the relevant phenotypes using advanced biochemical and cell biological techniques. This award will serve me as a springboard to achieve my career goal for being professor and my scientific goals of developing strategies to ameliorate human healthspan. The mentored portion of the award will provide me with the necessary skills to achieve scientific independence and accomplish my short-term scientific goal. To achieve that I will received the help of numerous collaborators but also from two mentors experts in the two respective fields (senescence with Dr. Judith Campisi and mice healthspan with Dr. Richard Miller). My two mentors will also help for my preparation to become an assistant professor in the field of aging both at the scientific and personal level. In addition during the mentored phase I will take an intensive histology class from UC Davis. I will then be fully armed to embrace the independent portion of the award where I will continue studying the effects that S6K2 depletion on cellular senescence in vivo and its role on mice healthspan.

描述（由申请人提供）：由蛋白质TOR（雷帕霉素的靶标）控制的营养感应途径的调节导致各种生物的寿命延长。这一发现对人类具有出色的潜在健康益处。但是，未能理解其作用机制已减缓其对临床健康范围福利的应用。哺乳动物TOR复合物1（MTORC1）可以用化合物雷帕霉素在药理上抑制。雷帕霉素主要通过S6激酶1和2（S6K1和S6K2）抑制特定的TOR活性子集。雷帕霉素延长了雄性和雌性小鼠的寿命，但也通过未知机制对健康产生负面影响。 S6K1缺乏的雌性小鼠（但不是雄性小鼠）具有延长的寿命，在雷帕霉素的寿命扩展中，其他激酶S6K2的作用表明了作用。同样，没有关于S6K2缺陷小鼠的寿命的数据。有趣的是，S6K2已与保护细胞免受细胞凋亡有关。另一个，肿瘤抑制机制是细胞衰老（永久性细胞生长停滞计划）。表达S6K2的细胞可能有利于衰老，而不是细胞凋亡，作为预防肿瘤幻影的机制。随着年龄的增长，细胞衰老的积累被广泛视为衰老表型的贡献。这些细胞分泌促炎性细胞因子一种称为衰老相关的分泌表型SASP的表型，因此，它们在衰老生物体中的积累可能会导致已知的慢性炎症，从而刺激与年龄相关的病理的幻影。最近，据表明，衰老细胞的间隙减轻了后代小鼠模型中与年龄相关的表型。我的初步数据表明，在培养中的衰老细胞中，雷帕霉素降低了这些促炎性细胞因子的产生，并且通过下调S6K2而不是S6K1获得了相似的结果。我的假设是，S6K2活性的降低通过减轻衰老小鼠的衰老表型来扩展健康和寿命。我的研究建议将检验以下假设：雷帕霉素或其他手段通过抑制S6K2活性来减少SASP，尤其是其促炎的SASP。我将进一步检验以下假设：S6K2活性的抑制会导致小鼠延长寿命和健康状态。此外，我将探讨S6K2作用并确定其主要底物的机制。我将通过评估细胞，组织表型以及S6K2缺乏细胞和小鼠的生理学以及表达S6K2表达或耗尽的人类成纤维细胞来实现这些目标。我将使用晚期生化和细胞生物学技术检查细胞，组织和动物的相关表型。该奖项将成为我的跳板，以实现我的职业目标，以成为教授的职业目标以及制定改善人类健康范围的策略的科学目标。该奖项的指导部分将为我提供实现科学独立性并实现我短期科学目标的必要技能。为此，我将收到众多合作者的帮助，但也来自两个各个领域的导师专家（与Richard Miller博士一起与Judith Campisi博士和Mice Healthspan的衰老）。我的两位导师还将有助于我准备成为科学和个人层面上衰老领域的助理教授。此外，在指导阶段，我将参加加州大学戴维斯分校的密集组织学课程。然后，我将完全武装着奖励的独立部分，在那里我将继续研究S6K2耗竭对体内细胞衰老及其对MICE HealthSpan的作用的影响。