Lysosomal Enzymes and Associated Human Genetic Diseases

溶酶体酶和相关人类遗传疾病

• 批准号: 7798945
• 负责人: PETER LOBEL
• 金额: $ 38.61万
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-06-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798945
• 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）： 溶酶体是一种酸性的、膜界定的细胞器，其主要功能是降解大分子。溶酶体含有多种可溶性酶，其水解底物以及跨膜蛋白，其执行许多功能，包括将降解产物转运出该细胞器。数十种溶酶体储积症（LSD）（例如泰-萨氏病）说明了溶酶体蛋白在正常细胞生理学中的重要性，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的疾病，包括精神发育迟滞，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，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展，但仍有许多工作要做，因为有许多临床定义的疾病似乎是LSD，但其分子病因不明。此外，根据临床和超微结构标准，有许多个体患有LSD，但尚未确定其基因缺陷。我们假设这些未解决的遗传疾病中有许多是由编码溶酶体蛋白的基因突变引起的。这项建议的总体目标是确定这些未解决的LSD案件的基础。有两个具体目标。目的1是使用一种新开发的比较蛋白质组学方法，以确定异常蛋白质和基因缺陷的基础上许多未解决的LSD。目的2是使用定量质谱与亚细胞分级，以确定溶酶体蛋白质组，并使这些信息容易获得的生物医学界。这将建立一个资源，将大大促进识别溶酶体疾病基因使用其他方法，如连锁分析。这些特定目标的完成将确定新的溶酶体疾病基因以及现有疾病基因中引起非典型临床表现的新突变。这对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对广泛存在的人类疾病的研究成为可能，其中溶酶体变化可能是重要的，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。拟议的研究是确定以前未解决的人类遗传疾病的基础。这项研究还将建立一个系统，用于调查一组生物医学上重要的蛋白质在阿尔茨海默氏症和癌症等广泛的人类疾病中的作用。