Cell non-autonomous nature of the heat shock response

细胞热激反应的非自主性

• 批准号: 8581823
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581823
• 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）：对组织或生物体中不同细胞类型之间的同步通信以达到正常功能。离散组织中产生的各种分泌的细胞外信号通常具有影响整个生物体中稳态的潜力。有时，这些信号可能具有破坏性：例如，在许多年龄发作的神经退行性疾病中，功能障碍会在确定的神经元子集中产生，随后在外周组织中启动退化性级联反应。然而，从一个组织到另一种组织的信号也可以是建设性的，并以对生物体的坐标保护结束。 道格拉斯博士已经确定了起源于神经系统的转导信号传导成分，并可以赋予远端相关组织中的压力的​​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仅在线虫的神经系统中。秀丽隐杆线虫：（1）防止热应激； （2）减慢衰老； （3）远端组织中的模型 - 蛋白酶蛋白质解毒。分泌的HSF-1信号赋予的热保护需要功能性的热感神经回路和RNA转运蛋白，这表明其传播需要推定的RNA信号。相比之下，长叶和蛋白 - 氧化表型需要一个独特的信号通路，以使其传播涉及胰岛素/IGF-1转录因子DAF-16。因此，神经系统中HSF-1激活的位点和性质指定其针对不同压力源的保护方式。 在这项研究中，道格拉斯博士将表征生物完整的生物中这些细胞外信号事件的产生，传播和最终接收。在AIM 1中，他将确定能够分泌保护性HSF-1信号并定义这些精选神经元中的参与机械的关键神经元。在AIM 2中，将发现每个发散信号的身份。在AIM 3中，将在受体组织中识别出细胞因素，以识别不同的HSF-1信号并启动保护程序。 在指导阶段进行的培训将使道格拉斯博士使用良好的发达且易于处理的遗传学，神经生物学和秀丽隐杆线虫的生物化学来指导一个独立的实验室，以解决生物学重要性的新问题。该奖项下的培训将包括：学习利用秀丽隐杆线虫神经系统研究完整动物中神经出生的细胞外信号传导事件；定量蛋白质组学中的质谱技术是确定相关信号分子和相关机械所必需的；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；以及教学和授予写作等指导能力。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。