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

项目摘要/摘要： 细胞程序性死亡或凋亡是一个自然的发育过程。细胞凋亡失败可导致 发育异常、癌症(失控生长)和自身免疫性疾病，虽然过度 细胞凋亡与阿尔茨海默氏症和帕金森氏症等神经退行性疾病有关。 细胞凋亡的不同阶段(启动、执行和吞噬)继续被识别，这表明我们的 对细胞凋亡发生和调控的机制仍缺乏了解。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、活体观察生殖系中的细胞凋亡(生理或应激诱导的生殖系细胞凋亡)。 我们最近在线虫中发现了一个保守的RNA结合蛋白(RBP)，属于高度 保守的CELF/Bruno蛋白家族ETR-1在生殖细胞凋亡中发挥作用。初步调查结果 表明ETR-1的耗尽会导致生殖系凋亡细胞的积累，并且 细胞凋亡吞噬途径是ETR-1潜在的信使核糖核酸靶点。这项提议的总体目标 本研究旨在阐明ETR-1‘S在生殖系细胞凋亡中的作用及其作用机制 在细胞凋亡过程中。指导这项拟议工作的中心假设是ETR-1在RNA结合中发挥作用 在生理性生殖细胞凋亡早期阶段依赖的方式来调节执行，还 在吞噬的后期。这项研究的基本原理是，成功完成这项研究将有助于 我们在多个层面上对细胞凋亡的基本理解。为了检验中心假说，我们设计了 有两个明确的目标。具体目标1将集中在确定ETR-1在生理或应激中的作用- 检测ETR-1缺失诱导细胞凋亡的动力学及组织特异性 性腺中与细胞凋亡相关的ETR-1的需求。具体目标2将侧重于了解 ETR-1的RNA识别基序(RRM)结构域在生殖系细胞凋亡中的作用拟议中的工作 是创新的，因为我们将在体内阐明一个新的凋亡参与者在完整的多细胞中的作用 生物体，并确定以前未表征的RNA结合蛋白的mRNA靶标。完成 这些目标将使我们更深入地了解细胞凋亡的过程以及细胞凋亡是如何 控制得当。这项建议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的兴趣。这项建议将促进 在主要的HBCU霍华德大学，早期职业生涯中代表不足的少数族裔学生 (历史上的黑人学院和大学)。这项研究具有很强的针对性