Cell Non-Autonomous nature of the Heat Shock Response

热激反应的细胞非自主性

基本信息

批准号：
9310369
负责人：
Peter Mahan Douglas
金额：
$ 23.61万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310369
关键词：
Address Age of Onset Aging Anatomy Animals Area Automobile Driving Award Biochemistry Bioinformatics Biological Caenorhabditis elegans Cells Communication DNA Sequence Alteration Data Disease Disease model Distal Drug Metabolic Detoxication Educational process of instructing Ensure Event Functional disorder Generations Genes Genetic Goals Grant Heat Stress Disorders Heat-Shock Response Homeostasis Insulin Insulin-Like Growth Factor I Investigation Learning 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 knock-down neural circuit programs proteostasis public health relevance relating to nervous system response ribosome profiling skills stressor success transcription factor

项目摘要

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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

星形胶质细胞的糖酵解预处理可减轻创伤引起的神经变性。

DOI：
发表时间：
2021
期刊：
影响因子：
7.7
作者：
Solano Fonseca, Rene;Metang, Patrick;Egge, Nathan;Liu, Yingjian;Zuurbier, Kielen R;Sivaprakasam, Karthigayini;Shirazi, Shawn;Chuah, Ashleigh;Arneaud, Sonja Lb;Konopka, Genevieve;Qian, Dong;Douglas, Peter M
通讯作者：
Douglas, Peter M

Trauma-induced regulation of VHP-1 modulates the cellular response to mechanical stress.

创伤诱导的 VHP-1 调节可调节细胞对机械应力的反应。

DOI：
发表时间：
2021-03-05
期刊：
影响因子：
16.6
作者：
Egge, Nathan;Arneaud, Sonja L B;Fonseca, Rene Solano;Zuurbier, Kielen R;McClendon, Jacob;Douglas, Peter M
通讯作者：
Douglas, Peter M

Intracellular lipid surveillance by small G protein geranylgeranylation.

通过小 G 蛋白香叶基香叶基化进行细胞内脂质监测。

DOI：
发表时间：
2022-05
期刊：
影响因子：
64.8
作者：
Watterson, Abigail;Tatge, Lexus;Wajahat, Naureen;Arneaud, Sonja L B;Solano Fonseca, Rene;Beheshti, Shaghayegh T;Metang, Patrick;Mihelakis, Melina;Zuurbier, Kielen R;Corley, Chase D;Dehghan, Ishmael;McDonald, Jeffrey G;Douglas, Peter M
通讯作者：
Douglas, Peter M

The stress response paradox: fighting degeneration at the cost of cancer.

压力反应悖论：以癌症为代价对抗退化。