Cell non-autonomous nature of the heat shock response

细胞热激反应的非自主性

• 批准号: 8735836
• 负责人: Peter Mahan Douglas
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735836
• 关键词: Address; Age of Onset; Aging; Anatomy; Animals; Area; Automobile Driving; Award; Biochemistry; Bioinformatics; Biological; Caenorhabditis elegans; Cells; Communication; Data; Disease; Disease model; Distal; Drug Metabolic Detoxication; Educational process of instructing; Ensure; Event; Functional disorder; Gene Mutation; Generations; Genes; Genetic; Goals; Grant; Heat Stress Disorders; Heat-Shock Response; Heating; Homeostasis; Insulin; Insulin-Like Growth Factor I; Learning; Life; Longevity; Mass Spectrum Analysis; Mediating; Mentors; Mentorship; Methods; Modeling; Molecular; Muscle; Nature; Nematoda; Nervous system structure; Neurobiology; Neurodegenerative Disorders; Neurons; Organism; Peripheral; Phase; Phenotype; Production; Proteins; Proteomics; RNA; Regulation; Research; Research Personnel; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Small RNA; Source; Specific qualifier value; Stress; Techniques; Tissues; Toxic effect; Training; Transgenes; Validation; Work; Writing; cell type; extracellular; heat shock transcription factor; neural circuit; programs; public health relevance; relating to nervous system; response; skills; stressor; success; transcription factor

DESCRIPTION (provided by applicant): The synchronous communication among different cell types within a tissue or organism to achieve normal function is poorly understood. A variety of secreted extracellular signals that are generated in discrete tissues often have the potential to impact homeostasis throughout the entire organism. Occasionally, these signals can be destructive: in numerous age-onset neurodegenerative diseases, for example, dysfunction arises in a defined subset of neurons and subsequently initiates a degenerative cascade in peripheral tissues. Yet, signals from one tissue to another can also be constructive and end in the coordinate protection of the organism. Dr. Douglas has identified a transduction signaling component that originates in the nervous system and can confer protection against stress in distally associated tissues. Preliminary studies show that expression of a constitutively-activated Heat Shock transcription Factor, HSF-1, exclusively in the nervous system of the nematode C. elegans: (1) protects against heat stress; (2) slows aging; and (3) detoxifies model-disease proteins in distal tissues. Heat-protection conferred by secreted HSF-1 signals requires a functional thermo- sensory neural circuit and RNA transporters, suggesting that a putative RNA signal is required for its propagation. In contrast, long-lifespan and proteo-detoxification phenotypes require a distinct signaling pathway for their propagation involving the insulin/IGF-1 transcription factor DAF-16. Thus the site and nature of HSF-1 activation in the nervous system specifies its mode of protection against different stressors. In this study, Dr. Douglas will characterize the generation, propagation and ultimate receipt of these extracellular signaling events in a living, intact organism. In Aim 1, he will identify key neurons which are capable of secreting protective HSF-1 signals and define the participating machinery within those select neurons. In Aim 2, the identity of each divergent signal will be uncovered. In Aim 3, cellular factors will be identified within recipient tissues which are required to recognize the different HSF-1 signals and initiate protective programs. Training in the mentored phase will prepare Dr. Douglas to direct an independent lab using the well developed and tractable genetics, neurobiology, and biochemistry of C. elegans to address new questions of biological importance. Training under this award will include: learning to utilize the C. elegans nervous system to study neural-born extracellular signaling events in the intact animal; mass spectrometry techniques in quantitative proteomics which are necessary to identify pertinent signaling molecules and associated machinery; bioinformatic techniques necessary for small RNA profiling and tissue-specific ribosomal profiling; new investigational methods in the fields of protein homeostasis and aging; and mentorship skills such as teaching and grant writing. These will greatly facilitate Dr. Douglas' transition and success as an independent investigator.

描述（由申请人提供）：组织或生物体内不同细胞类型之间实现正常功能的同步通信知之甚少。在离散组织中产生的各种分泌的细胞外信号通常有可能影响整个生物体的稳态。有时，这些信号可能具有破坏性：例如，在许多年龄相关的神经退行性疾病中，特定的神经元亚群会出现功能障碍，随后在周围组织中引发退行性级联反应。然而，从一个组织到另一个组织的信号也可以是建设性的，并最终实现对生物体的协调保护。 道格拉斯博士发现了一种源自神经系统的转导信号成分，可以为远端相关组织提供针对压力的保护。初步研究表明，组成型激活的表达 热休克转录因子 HSF-1，仅存在于线虫秀丽隐杆线虫的神经系统中：（1）防止热应激； (2)延缓衰老； (3)解毒远端组织中的模型疾病蛋白。分泌的 HSF-1 信号赋予的热保护需要功能性热感觉神经回路和 RNA 转运蛋白，这表明假定的 RNA 信号是其传播所必需的。相比之下，长寿命和蛋白质解毒表型需要独特的信号通路来传播，涉及胰岛素/IGF-1转录因子DAF-16。因此，神经系统中 HSF-1 激活的位点和性质决定了其针对不同应激源的保护模式。 在这项研究中，道格拉斯博士将描述活体完整生物体中这些细胞外信号事件的产生、传播和最终接收。在目标 1 中，他将识别能够分泌保护性 HSF-1 信号的关键神经元，并定义这些选定神经元内的参与机制。在目标 2 中，每个不同信号的身份将被揭露。在目标 3 中，将鉴定受体组织内识别不同 HSF-1 信号并启动保护程序所需的细胞因子。 指导阶段的培训将使道格拉斯博士准备好领导一个独立实验室，利用线虫成熟且易于处理的遗传学、神经生物学和生物化学来解决具有生物学重要性的新问题。该奖项的培训将包括：学习利用秀丽隐杆线虫神经系统来研究完整动物中神经产生的细胞外信号事件；定量蛋白质组学中的质谱技术对于识别相关信号分子和相关机制是必要的；小RNA分析和组织特异性核糖体分析所需的生物信息学技术；领域的新研究方法 蛋白质稳态和衰老；以及指导技能，例如教学和资助写作。这些将极大地促进道格拉斯博士作为独立研究者的过渡和成功。