Lysosomal Enzymes and Associated Human Genetic Diseases

溶酶体酶和相关人类遗传疾病

基本信息

批准号：
8709755
负责人：
PETER LOBEL
金额：
$ 5.69万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8709755
关键词：
Lysosomal Enzymes Associated Human Genetic

项目摘要

DESCRIPTION (provided by applicant): Lysosomes are acidic, membrane-delimited organelles whose central function is to degrade macromolecules. The lysosome contains a wide variety of soluble enzymes that hydrolyze substrates as well as transmembrane proteins that perform a number of functions including transport of degradation products out of this organelle. The importance of lysosomal proteins in normal cellular physiology is illustrated by the dozens of lysosomal storage disorders (LSDs) such as Tay-Sach's disease where a deficiency in a single lysosomal protein results in accumulation of catabolites and a depletion of downstream metabolites. These monogenic diseases typically cause severe illness including mental retardation, developmental deformities, and premature death. The gene defects in over 40 different LSDs have been identified, which, through genetic counseling, has greatly decreased the prevalence of some of these disorders. Despite this impressive progress, much remains to be accomplished as there are a number of clinically-defined disorders that appear to be LSDs but which are of unknown molecular etiology. In addition, there are numerous individuals that have LSDs based upon clinical and ultrastructural criteria for which the gene defects have not been identified. We hypothesize that many of these unsolved genetic diseases are caused by mutations in genes encoding lysosomal proteins. The overall goal of this proposal is to determine the basis of these unsolved LSD cases. There are two specific aims. Aim 1 is to use a newly developed comparative proteomics method to identify aberrant proteins and the gene defects underlying numerous unsolved LSDs. Aim 2 is to use quantitative mass spectrometry with subcellular fractionation to define the lysosomal proteome and to make this information readily accessible to the biomedical community. This will establish a resource that will greatly facilitate identification of lysosomal disease genes using other approaches such as linkage analysis. Completion of these specific aims will identify new lysosomal disease genes as well as new mutations in existing disease genes that cause atypical clinical presentations. This will be of paramount significant to the affected individuals and families, and will provide important information on how lysosomal deficiencies are manifested. In addition, the proteomics methods established to investigate LSDs will enable future studies on widespread human disorders where lysosomal changes may be important, including cancer and Alzheimer disease. Finally, assignment of the lysosomal proteome will be an important contribution to functional genomics and will have broad biomedical impact.The proposed research is to determine the basis for previously unsolved human genetic diseases. This research will also establish systems for the investigation of the role of a group of biomedically important proteins in widespread human diseases in such as Alzheimer's and cancer.

描述（由申请人提供）：溶酶体是酸性、膜界定的细胞器，其中心功能是降解大分子。溶酶体含有多种可水解底物的可溶性酶以及执行多种功能的跨膜蛋白，包括将降解产物转运出该细胞器。溶酶体蛋白在正常细胞生理学中的重要性可以通过数十种溶酶体贮积症 (LSD) 来说明，例如泰-萨赫病，其中单一溶酶体蛋白的缺乏会导致分解代谢物的积累和下游代谢物的消耗。这些单基因疾病通常会导致严重疾病，包括智力低下、发育畸形和过早死亡。超过 40 种不同的 LSD 的基因缺陷已被确定，通过遗传咨询，大大降低了其中一些疾病的患病率。尽管取得了这一令人印象深刻的进展，但仍有许多工作有待完成，因为有许多临床定义的疾病似乎是LSD，但其分子病因学未知。此外，根据临床和超微结构标准，许多人患有 LSD，但其基因缺陷尚未确定。我们假设许多未解决的遗传疾病是由编码溶酶体蛋白的基因突变引起的。该提案的总体目标是确定这些未解决的 LSD 案件的依据。有两个具体目标。目标 1 是使用新开发的比较蛋白质组学方法来识别异常蛋白质和众多未解决的 LSD 背后的基因缺陷。目标 2 是使用定量质谱法和亚细胞分级来定义溶酶体蛋白质组，并使生物医学界能够轻松获取此信息。这将建立一个资源，极大地促进使用连锁分析等其他方法鉴定溶酶体疾病基因。完成这些具体目标将识别新的溶酶体疾病基因以及现有疾病基因中导致非典型临床表现的新突变。这对于受影响的个人和家庭至关重要，并将提供有关溶酶体缺陷如何表现的重要信息。此外，为研究LSD而建立的蛋白质组学方法将使未来能够研究溶酶体变化可能很重要的广泛人类疾病，包括癌症和阿尔茨海默病。最后，溶酶体蛋白质组的分配将是对功能基因组学的重要贡献，并将产生广泛的生物医学影响。拟议的研究旨在确定以前未解决的人类遗传疾病的基础。这项研究还将建立系统来研究一组生物医学上重要的蛋白质在广泛的人类疾病（如阿尔茨海默病和癌症）中的作用。