BIOCHEMICAL AND MS CHARACTERIZATION OF WERNER PROTEIN INTERACTION NETWORK

Werner 蛋白质相互作用网络的生化和 MS 表征

• 批准号: 8171366
• 负责人: Michael MacCoss
• 金额: $ 0.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171366
• 关键词: Aging; Aging-Related Process; Biochemical; Biological; Cells; Complex; Computational Science; Computer Retrieval of Information on Scientific Projects Database; DNA Damage; Development; Diabetes Mellitus; Disease; Elderly; Event; Funding; Genes; Genome; Genomics; Grant; Human; Institution; Knowledge; Lead; Longevity; Malignant Neoplasms; Mutation; Organism; Osteoporosis; Pathogenesis; Pathology; Persons; Population; Post-Translational Protein Processing; Predisposition; Proteins; Proteomics; Research; Research Personnel; Resources; Sampling; Series; Source; United States National Institutes of Health; WRN gene; Werner Syndrome; Work; age related; demographics; environmental agent; helicase; improved; insight; instrumentation; interest; novel strategies; prevent; protein function; senescence

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our focus of research, the Werner protein, is one of disease-associated RecQ helicases. Its deficiency results in the Werner syndrome (WS), characterized by accelerated rate of mutation and the organism's inability to resolve a variety of genome-damaging events. Mutations in the WRN gene (also referred to as RECQ3 or RECQL2) don't appear to increase a person's susceptibility to DNA damage, and they alone do not cause the development of the disease. Instead they accelerate and exacerbate the disease that could develop even without this sensitizing mutation due to the damaging environmental agents. An important consequence of understanding the mechanism of a pathology is the ability to treat it more effectively, and even to prevent it in some cases. Aging research is extremely important considering the changing demographics worldwide, increased overall longevity and rise in elderly population. Understanding of the mechanisms that underlie aging and development of age-related disease due to genomic aberration can lead us to improved treatment and alleviated burden of age-related disease. Activity of proteins such as WRN suggests that the complex process of ageing is controlled by a conserved number of genes. However, mutations in a series of proteins do not suggest that their normal function is involved in promoting longevity. We are interested in understanding how normal function of this protein stalls senescence. In order to determine these mechanisms we study protein function in normal and diseased states with the use of proteomics. Resources that are currently available to us include modern analytical instrumentation, support from computational sciences, and access to rare biological samples. Our work is aimed at defining consistently associated proteins and post-translational modifications of WRN that are required or are causal for its function in human cells. This knowledge will increase our understanding of WS pathogenesis and provide insight into novel strategies to alter the progression of WS or associated diseases such as ASCVD, cancer, diabetes, and osteoporosis.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们的研究重点是Werner蛋白，是与疾病相关的RECQ解旋酶之一。它的缺乏导致Werner综合征（WS），其特征在于突变速率加速和生物体无法解决各种基因组损害事件的特征。 WRN基因中的突变（也称为RECQ3或RECQL2）似乎不会增加一个人对DNA损伤的敏感性，并且仅它们并不会引起疾病的发展。取而代之的是，它们加速并加剧了该疾病，即使没有破坏性的环境药物，这种疾病也可以发展出来。 理解病理机制的重要结果是能够更有效地治疗它，甚至在某些情况下可以防止它。考虑到全球人口统计学变化，总体寿命和老年人口的增长，衰老研究非常重要。了解由于基因组像差引起的与年龄相关疾病的衰老和发展的机制可能导致我们改善治疗并减轻与年龄相关疾病的负担。蛋白质（例如WRN）的活性表明，复杂的衰老过程由保守数量的基因控制。但是，一系列蛋白质中的突变并不表明它们的正常功能涉及促进寿命。我们有兴趣了解该蛋白质衰老的正常功能。 为了确定这些机制，我们通过使用蛋白质组学研究正常和患病状态的蛋白质功能。当前可供我们使用的资源包括现代分析仪器，计算科学的支持以及获得稀有生物样品的访问。我们的工作旨在定义始终相关的蛋白质和对WRN的翻译后修饰，或者是其在人类细胞中功能的因果关系。这些知识将增加我们对WS发病机理的理解，并提供对改变WS或相关疾病（例如ASCVD，癌症，糖尿病和骨质疏松症）的新型策略的见解。