Lysosomal Enzymes and Associated Human Genetic Diseases

溶酶体酶和相关人类遗传疾病

• 批准号: 7992517
• 负责人: PETER LOBEL
• 金额: $ 9.32万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992517
• 关键词: Affect; Alzheimer' s Disease; Cell Fractionation; Cell physiology; Cessation of life; Clinical; Communities; Defect; Deformity; Development; Disease; Enzymes; Etiology; Family; Future; Gene Proteins; Genes; Genetic Counseling; Goals; Hereditary Disease; Human; Human Genetics; Hydrolysis; Individual; Integral Membrane Protein; Investigation; Lysosomes; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Mental Retardation; Methods; Molecular; Mutation; Organelles; Prevalence; Proteins; Proteome; Proteomics; Research; Resources; Role; System; Tay-Sachs Disease; base; comparative; disease-causing mutation; functional genomics; genetic linkage analysis; human disease; lysosomal proteins; macromolecule; premature

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）： 溶酶体是酸性的，膜脱落的细胞器，其中心功能是降解大分子。溶酶体含有多种可溶性酶，这些酶水解底物以及跨膜蛋白，它们执行许多功能，包括从该细胞器中运输降解产物。溶酶体蛋白在正常细胞生理学中的重要性通过数十种溶酶体储存障碍（LSD）（例如Tay-Sach的疾病）所说明，其中单个溶酶体蛋白质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引起严重疾病，包括智力低下，发育畸形和过早死亡。已经确定了40多种不同LSD的基因缺陷，通过遗传咨询，这些缺陷大大降低了其中一些疾病的患病率。尽管取得了令人印象深刻的进步，但仍有许多临床定义的疾病似乎是LSD，但它们是未知的分子病因。此外，有许多人具有基于临床和超微结构标准的LSD，尚未确定基因缺陷。我们假设这些未解决的遗传疾病中的许多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病例的基础。有两个具体的目标。目的1是使用新开发的比较蛋白质组学方法来鉴定异常蛋白质和基因缺陷，这些缺陷是众多未解决的LSD的基础。 AIM 2是使用具有亚细胞分级分级的定量质谱法来定义溶酶体蛋白质组，并使生物医学群落可以轻松访问此信息。这将建立一种资源，该资源将大大促进使用其他方法（例如链接分析）鉴定溶酶体疾病基因。这些特定目标的完成将确定新的溶酶体疾病基因以及引起非典型临床表现的现有疾病基因的新突变。这对受影响的个体和家庭至关重要，并将提供有关如何表现溶酶体缺陷的重要信息。此外，为研究LSD而建立的蛋白质组学方法将使未来的有关溶酶体变化可能很重要的人类疾病的研究，包括癌症和阿尔茨海默氏病。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，并将具有广泛的生物医学影响。该研究是确定先前未解决的人类遗传疾病的基础。这项研究还将建立调查一组生物医学重要蛋白在阿尔茨海默氏症和癌症等广泛人类疾病中的作用的系统。