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： 程序性细胞死亡或凋亡是自然发育过程。凋亡失败会导致 发育异常，癌症（不受控制的生长）和自身免疫性疾病，而过多 凋亡有助于神经退行性疾病，例如阿尔茨海默氏症和帕金森氏症。新球员 凋亡的各个阶段（启动，执行和吞噬）继续被确定，表明我们的 了解凋亡发生并受到调节的机制的理解仍然缺乏。秀丽隐杆线虫是 理想适合解决凋亡研究问题的遗传系统，因为透明的动物允许 实时，在体内观察种系中凋亡（生理或应激诱导的种系细胞凋亡）。 我们最近确定了属于高度的秀丽隐杆线虫中保存良好的RNA结合蛋白（RBP） 保守的CELF/BRUNO蛋白质家族ETR-1作为种系凋亡中的作用。初步发现 表明ETR-1的耗竭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靶标。该提议的总体目标 研究是为了阐明在种系凋亡过程中ETR-1的功能，以及ETR-1起作用的机制 在凋亡期间。指导拟议工作的中心假设是ETR-1在RNA结合中起作用 在生理种系细胞凋亡的早期阶段的依赖方式以调节执行以及 在后期吞噬的阶段。这项研究的理由是成功完成将有助于 我们对多个级别凋亡的基本理解。为了检验中心假设，我们已经设计了 两个具体的目标。具体目标1将集中于确定ETR-1在生理或应激中的作用 通过检查ETR-1耗竭和组织特异性的细胞凋亡动力学引起的凋亡 与凋亡有关的性腺中ETR-1的需求。具体目标2将专注于理解 生殖线凋亡过程中ETR-1的RNA识别基序（RRM）结构域的功能。拟议的工作 具有创新性，因为我们将在体内阐明新型凋亡玩家的作用 生物体，并确定先前未表征的RNA结合蛋白的mRNA靶标。完成 这些目标将对凋亡过程以及细胞凋亡的过程有更透彻的了解 正确控制。该建议的另一个重要长期目标是培养本科生 对生物医学研究领域的兴趣。该建议将有助于大量参与 在霍华德大学（Howard University）的职业生涯早期，代表性不足的少数族裔学生是主要的HBCU （历史上是黑人学院和大学）。这项研究很强