Regulation of Heat Shock Transcription Factor in Long-lived Animals

长寿动物热激转录因子的调节

• 批准号: 8669895
• 负责人: Ao-Lin Allen Hsu
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669895
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Affect; Age; Age of Onset; Aging; Aging-Related Process; Animal Model; Animals; Biochemical; Biological; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Cells; Cessation of life; Complex; Disease; Effectiveness; Genetic; Genetic Screening; Goals; Heat Stress Disorders; Heat shock proteins; Heat-Shock Response; Homeostasis; Insulin; Insulin-Like Growth Factor I; Invertebrates; Knowledge; Life; Link; Longevity; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Molecular; Molecular Chaperones; Mutation; Nematoda; Neurodegenerative Disorders; Organism; Oxidative Stress; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Process; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Reading; Regulation; Regulatory Pathway; Reporting; Research; Resistance; Role; Signal Pathway; Signal Transduction; Stress; System; Threonine; Tissues; age related; base; combat; genetic analysis; genetic manipulation; heat shock transcription factor; in vivo; mortality; mutant; novel; novel therapeutics; overexpression; protein complex; public health relevance; receptor; response; transcription factor

DESCRIPTION (provided by applicant): Extended longevity is often correlated with increased resistance against the deleterious effects of environmental and physiological stresses, including heat and oxidative stresses. Our previous results suggested that the C. elegans heat-shock transcription factor (HSF-1), a master regulator of the cellular response to heat stress, is under direct regulation of the insulin/IGF-1-like signaling (IIS) networks to modulate the rate of aging and the onset of age-related diseases associated with proteotoxicity. The ultimate goal of our research is to develop new therapeutic strategies for combating age-related disease by understanding how HSF-1 influences the aging process. We have previously demonstrated that the rate of aging can be influenced by the level of HSF-1 activity in C. elegans, and that HSF-1 activity is required for daf-2 mutations to extend lifespan. Our recent findings suggest that IIS may control HSF-1 activity by regulating the formation of an inhibitory protein heterocomplex (DHIC) containing HSF-1, HSB-1, and two novel HSF-1 regulators, DDL-1 and -2. We found that the formation of DHIC is largely inhibited when IIS is reduced or when DDL-1 is phosphorylated at the T182 residue. We also found that the phosphorylation status of DDL-1 is regulated by IIS. Based on these observations, this proposal will focus on: 1) Further defining the role of DHIC complex in HSF-1 regulation. In this aim, we will develop a BiFC reporting system to verify the formation of DHIC in vivo and use it as a read-out to identify additional regulators of DHIC formation. We will also determine the structural requirements for the DHIC complex formation. 2) Determining the mechanism by which IIS regulates DDL-1 phosphorylation and DHIC formation. In the proposed studies, we will determine how the IIS pathway regulates DDL-1 phosphorylation and the formation of DHIC. 3) Identifying and characterizing additional regulators and effectors of HSF-1. Both heat-shock and reduction of IIS promotes an increase in the post- translational modifications (PTM) of HSF-1. In this aim, we will investigate the impacts of these PTMs on HSF- 1 activity. In addition, we will further characterize a number of novel HSF-1 regulators previously identified from a genetic screen.

描述（由申请人提供）：寿命的延长通常与对环境和生理应激（包括热和氧化应激）有害影响的抵抗力增强相关。我们之前的结果表明，线虫热休克转录因子（HSF-1）是细胞对热应激反应的主要调节因子，受到胰岛素/IGF-1样信号传导（IIS）网络的直接调节，以调节衰老速度和与蛋白质毒性相关的年龄相关疾病的发生。我们研究的最终目标是通过了解 HSF-1 如何影响衰老过程来开发新的治疗策略来对抗与年龄相关的疾病。我们之前已经证明，秀丽隐杆线虫的衰老速度可能受到HSF-1活性水平的影响，并且HSF-1活性是daf-2突变延长寿命所必需的。我们最近的研究结果表明，IIS 可能通过调节包含 HSF-1、HSB-1 和两个新型 HSF-1 调节因子 DDL-1 和 -2 的抑制性蛋白杂复合物 (DHIC) 的形成来控制 HSF-1 活性。我们发现当 IIS 减少或 DDL-1 在 T182 残基处磷酸化时，DHIC 的形成在很大程度上受到抑制。我们还发现DDL-1的磷酸化状态受到IIS的调节。基于这些观察，该提案将重点关注：1）进一步明确DHIC复合物在HSF-1调节中的作用。为此，我们将开发一个 BiFC 报告系统来验证体内 DHIC 的形成，并将其用作读数来识别 DHIC 形成的其他调节因子。我们还将确定 DHIC 复合体形成的结构要求。 2)确定IIS调节DDL-1磷酸化和DHIC形成的机制。在拟议的研究中，我们将确定 IIS 途径如何调节 DDL-1 磷酸化和 DHIC 的形成。 3) 识别和表征 HSF-1 的其他调节因子和效应因子。热休克和 IIS 的减少都会促进 HSF-1 翻译后修饰 (PTM) 的增加。为此，我们将研究这些 PTM 对 HSF-1 活性的影响。此外，我们将进一步表征先前通过基因筛选鉴定的一些新型 HSF-1 调节剂。