Uncovering novel mechanisms of the CELF/Bruno protein ETR-1 in apoptosis

揭示 CELF/Bruno 蛋白 ETR-1 在细胞凋亡中的新机制

• 批准号: 10515071
• 负责人: Courtney Robinson
• 金额: $ 42.42万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515071
• 关键词: Address; Affect; Alzheimer' s Disease; Animals; Apoptosis; Apoptotic; Area; Autoimmune Diseases; Binding; Biological Models; Biomedical Research; Caenorhabditis elegans; Cell physiology; Cells; Development; Developmental Process; Disease; Environment; Failure; Fertility; Fostering; Functional disorder; Gene Abnormality; Gene Expression; Genetic; Genetic Transcription; Germ Cells; Germ Lines; Goals; Gonadal structure; Grant; Growth; Health; Historically Black Colleges and Universities; Human; Kinetics; Knowledge; Laboratories; Lead; Malignant Neoplasms; Messenger RNA; Minority Groups; Mission; Modeling; Molecular; Muscular Dystrophies; Nematoda; Neurodegenerative Disorders; Oogenesis; Organism; Parkinson Disease; Pathway interactions; Physiological; Play; Process; Protein Family; Proteins; RNA; RNA Binding; RNA Recognition Motif; RNA-Binding Proteins; Regulator Genes; Research; Role; Societies; Stress; Students; System; Testing; Time; Tissues; United States National Institutes of Health; Universities; Work; career; experience; graduate student; human disease; in vivo; innovation; insight; interest; member; nervous system disorder; novel; protein function; protein protein interaction; public health relevance; undergraduate student; underrepresented minority student

PROJECT SUMMARY/ABSTRACT: Programmed cell death or apoptosis is a natural developmental process. Failure of apoptosis can lead to developmental abnormalities, cancer (uncontrolled growth) and autoimmune diseases, while excessive apoptosis contributes to neurodegenerative diseases like Alzheimer's and Parkinson's. New players in the various stages of apoptosis (initiation, execution, and engulfment) continue to be identified, indicating that our understanding of the mechanism by which apoptosis occurs and is regulated is still lacking. C. elegans is an ideally suited genetic system to address apoptotic research questions because the transparent animals allows real time, in vivo, observation of apoptosis in the germline (physiological or stress-induced germline apoptosis). We recently identified a well-conserved RNA-binding protein (RBP) in C. elegans belonging to the highly conserved CELF/Bruno protein family, ETR-1, as playing a role in germline apoptosis. Preliminary findings show that depletion of ETR-1 results in accumulation of germline apoptotic cells and that a member of the apoptotic engulfment pathway is a potential mRNA target of ETR-1. The overall objective of this proposed study is to elucidate ETR-1's function during germline apoptosis, and the mechanism by which ETR-1 acts during apoptosis. The central hypothesis guiding the proposed work is that ETR-1 functions in a RNA-binding dependent manner during the early stages of physiological germline apoptosis to regulate execution and also in the later stage of engulfment. The rationale for this research is that successful completion will contribute to our fundamental understanding of apoptosis at multiple levels. To test the central hypothesis, we have devised two specific aims. Specific Aim 1 will focus on determining the role of ETR-1 in either physiological or stress- induced apoptosis through examining the kinetics of apoptosis upon ETR-1 depletion and the tissue specific requirement of ETR-1 in the gonad as related to apoptosis. Specific Aim 2 will focus on understanding the function of the RNA Recognition Motif (RRM) domains of ETR-1 during germline apoptosis. The proposed work is innovative because we will be elucidating in vivo the role for a novel apoptotic player in an intact multicellular organism, and identifying mRNA targets for a previously uncharacterized RNA-binding protein. Completion of these aims will provide a more thorough understanding of the process of apoptosis, and how apoptosis is properly controlled. Another important long-term goal of this proposal is to foster undergraduate student interest in the area of biomedical research. This proposal will facilitate substantial participation of underrepresented minority students in their early career years at Howard University, a major HBCU (Historically Black Colleges and Universities). This research has strong

项目概要/摘要： 程序性细胞死亡或细胞凋亡是自然发育过程。细胞凋亡失败可导致 发育异常、癌症（不受控制的生长）和自身免疫性疾病，而过度 细胞凋亡会导致阿尔茨海默病和帕金森病等神经退行性疾病。新玩家在 细胞凋亡的各个阶段（启动、执行和吞噬）不断被识别，这表明我们的细胞凋亡 对于细胞凋亡发生和调节的机制仍缺乏了解。线虫是一种 非常适合解决细胞凋亡研究问题的遗传系统，因为透明的动物允许 实时体内观察种系细胞凋亡（生理或应激诱导的种系细胞凋亡）。 我们最近在秀丽隐杆线虫中发现了一种高度保守的RNA结合蛋白（RBP），该蛋白属于高度保守的线虫。 保守的 CELF/Bruno 蛋白家族 ETR-1 在种系细胞凋亡中发挥作用。初步调查结果 表明 ETR-1 的耗尽会导致种系凋亡细胞的积累，并且 凋亡吞噬途径是 ETR-1 的潜在 mRNA 靶点。本提议的总体目标 研究旨在阐明ETR-1在种系细胞凋亡过程中的功能，以及ETR-1的作用机制 细胞凋亡期间。指导拟议工作的中心假设是 ETR-1 在 RNA 结合中发挥作用 在生理种系细胞凋亡的早期阶段以依赖的方式调节执行，并且 在吞噬的后期。这项研究的基本原理是成功完成将有助于 我们对多个层面的细胞凋亡的基本理解。为了检验中心假设，我们设计了 两个具体目标。具体目标 1 将重点确定 ETR-1 在生理或压力中的作用 通过检查 ETR-1 耗尽时的细胞凋亡动力学和组织特异性来诱导细胞凋亡 性腺中 ETR-1 的需求与细胞凋亡有关。具体目标 2 将侧重于理解 ETR-1 的 RNA 识别基序 (RRM) 结构域在种系细胞凋亡过程中的功能。拟议的工作 具有创新性，因为我们将在体内阐明新型凋亡因子在完整多细胞中的作用 有机体，并识别先前未表征的 RNA 结合蛋白的 mRNA 靶标。完成 这些目标将提供对细胞凋亡过程以及细胞凋亡如何发生的更透彻的了解。 适当控制。该提案的另一个重要的长期目标是培养本科生 对生物医学研究领域感兴趣。该提案将促进大量参与 霍华德大学是一所主要的 HBCU，少数族裔学生在其早期职业生涯中代表性不足 （历史上的黑人学院和大学）。这项研究具有很强的