Mechanisms of protein turnover in apoptosis

细胞凋亡中蛋白质周转的机制

基本信息

批准号：
7183603
负责人：
JOHN ROBERT NAMBU
金额：
$ 21.41万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7183603
关键词：
Address Adult Age Aging Aging-Related Process Apoptosis Behavioral Binding Biochemical Biochemical Genetics Biochemical Pathway Biological Biological Models Caenorhabditis elegans Caspase Caspase Inhibitor Cell Death Cell Survival Cell physiology Cells Cessation of life Complex Development Disease Drosophila genus Drosophila melanogaster Exhibits F Box Domain Gene Combinations Genes Genetic Goals Human Invertebrates Life Cycle Stages Longevity Malignant Neoplasms Mammalian Cell Modeling Molecular Genetics Mutation Nematoda Nerve Degeneration Nervous System Physiology Nervous system structure Neuroglia Neurons Pathway interactions Pattern Phenotype Physiological Principal Investigator Process Property Proteins Regulation Role Stimulus Tertiary Protein Structure Ubiquitin Ubiquitination age related base fly gamma-Glutamyl Hydrolase inhibitor/antagonist insight multicatalytic endopeptidase complex mutant nervous system disorder novel programs protein degradation protein function relating to nervous system tissue culture ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to better understand the roles of programmed cell death and protein turnover in the aging process. Towards this end we will focus our studies on analyses of these processes in the nervous system of Drosophila, a powerful molecular genetic model system. We will utilize a battery of genetic, biochemical, and cell biological approaches to address two major issues. The first is to understand the basis for functional interactions between Morgue, a novel F box/ubiquitin conjugase domain protein, and Effete/UbcD1, a highly conserved ubiquitin E2 conjugase. Both proteins have pro-cell death functions and can bind to and promote the turnover of DIAP1, an essential caspase inhibitor. Mutations in these genes exhibit strong genetic interactions and suggest that the two proteins function closely together to regulate nervous system cell survival and progression of flies through the life cycle. We will carefully analyze the cellular and behavioral phenotypes of various mutant combinations of these genes, as well as determine if the proteins act together in a ubiquitination complex. In addition we will analyze the ability of these proteins to promote cell death in Drosophila tissue and cultured mammalian cells. The second issue we address is to illuminate the relationship between cell death and aging in the Drosophila nervous system. Towards this end, we will document the patterns of cell death in wild type and mutant flies that exhibit altered lifespan and aging properties, elucidate the importance of nervous system cell death in influencing lifespan, and determine if neurons or glia exhibit altered abilities to die as they age. These studies will help illuminate the roles of the ubiquitin/proteasome pathway of protein turnover in programmed cell death and in turn, how changes in the propensity or ability of cells in the aging nervous system to die may influence nervous system function and life span. Significantly, studies in invertebrate model systems, such as the nematode Caenorhabditis elegans and fruit fly, Drosophila melanogaster, have provided invaluable insight into the genetic pathways and biochemical mechanisms of cell death and aging processes. As there exists many devastating late onset human neurological diseases, such as neural or glial cancers and neurodegeneration disorders, the results from these studies will| not only provide new insight into fundamental cellular processes, but will also have important biomedical relevance.

描述（由申请人提供）：该提案的总体目标是更好地了解程序性细胞死亡和蛋白质周转在衰老过程中的作用。为此，我们将集中研究分析果蝇神经系统中的这些过程，果蝇是一个强大的分子遗传模型系统。我们将利用一系列遗传、生化和细胞生物学方法来解决两个主要问题。首先是了解 Morgue（一种新型 F 盒/泛素缀合酶结构域蛋白）和 Effete/UbcD1（一种高度保守的泛素 E2 缀合酶）之间功能相互作用的基础。这两种蛋白都具有促细胞死亡功能，并且可以结合并促进 DIAP1（一种重要的半胱天冬酶抑制剂）的周转。这些基因的突变表现出强烈的遗传相互作用，表明这两种蛋白质密切合作，调节果蝇整个生命周期的神经系统细胞存活和进展。我们将仔细分析这些基因的各种突变组合的细胞和行为表型，并确定这些蛋白质是否在泛素化复合物中共同作用。此外，我们将分析这些蛋白质促进果蝇组织和培养的哺乳动物细胞细胞死亡的能力。我们解决的第二个问题是阐明果蝇神经系统细胞死亡和衰老之间的关系。为此，我们将记录野生型和突变果蝇的细胞死亡模式，这些模式表现出改变的寿命和衰老特性，阐明神经系统细胞死亡在影响寿命方面的重要性，并确定神经元或神经胶质细胞是否表现出改变的死亡能力他们变老了。这些研究将有助于阐明蛋白质周转的泛素/蛋白酶体途径在程序性细胞死亡中的作用，进而阐明衰老神经系统中细胞死亡倾向或能力的变化如何影响神经系统功能和寿命。值得注意的是，对无脊椎动物模型系统（例如线虫秀丽隐杆线虫和果蝇果蝇）的研究为细胞死亡和衰老过程的遗传途径和生化机制提供了宝贵的见解。由于存在许多毁灭性的迟发性人类神经系统疾病，例如神经或神经胶质癌和神经退行性疾病，这些研究的结果将|不仅提供了对基本细胞过程的新见解，而且还具有重要的生物医学意义。