MOLECULAR BASIS OF FAMILIAL STUTTERING

家族性口吃的分子基础

基本信息

批准号：
8189090
负责人：
STUART A KORNFELD
金额：
$ 22.8万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189090
关键词：
Acetylglucosamine Acids Affect Biogenesis Biological Assay Cathepsins Cell Extracts Cells Communication Complementary DNA Defect Disease Dominant-Negative Mutation Enzymes Exhibits Fibroblasts Functional disorder Genes Genetic Glycoproteins Goals Half-Life Hela Cells Hour Human Hydrolase I-Cell Disease Impairment Incubated Individual Label Lead Life Lysosomal Storage Diseases Lysosomes Mannose Measures Men&apos s Role Missense Mutation Molecular Mutation N acetylglucosaminidase N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase Neurons Pathologic Pathway interactions Patients Phenotype Phosphotransferases Physiologic pulse Population Population Decreases Proteins Pseudo-Hurler Polydystrophy Research Serum-Free Culture Media Signal Transduction Sorting - Cell Movement Stuttering System Testing Transfection base falls man mannose 6 phosphate meetings mutant phosphodiester protein folding relating to nervous system research study trafficking

项目摘要

DESCRIPTION (provided by applicant): A recent study of the genetic basis of persistent stuttering identified 10 mutations in the three genes that encode the two enzymes that add a Mannose 6-phosphate tag onto newly synthesized lysosomal acid hydrolases. This tag serves to direct ("target") the acid hydrolases to lysosomes. The objective of this research is to determine the effect of the mutations found in the stuttering population on the acid hydrolase targeting pathway. The hypothesis is that these mutations impair lysosomal function in neurons that are involved in stuttering, thereby damaging these critical cells. Patient fibroblasts will be used for these studies as surrogates for the neurons and the synthesis of the Man-6-P tag will be studied in a variety of ways. In addition, cells will be transfected with cDNAs encoding the mutant forms of the enzymes to follow potential effects on protein folding, trafficking, localization and half-life. The overall goal is to obtain an understanding of the cellular abnormalities that lead to stuttering. PUBLIC HEALTH RELEVANCE: This research is directly relevant to the molecular understanding of how mutations in the genes that encode proteins involved in the biogenesis of lysosomes lead to familial stuttering, a relatively common condition the impairs communication and has life altering effects.

描述（由申请人提供）：对持续口吃的遗传基础的最新研究鉴定出了三个基因中的10个突变，这些基因编码了将甘露糖6-磷酸标签添加到新合成的溶酶体酸水解酶中的两种酶。该标签用于将酸水解酶引导到溶酶体。这项研究的目的是确定口吃种群中突变对酸水解酶靶向途径的影响。假设是这些突变会损害与口吃相关的神经元中的溶酶体功能，从而损害了这些关键细胞。这些研究将使用患者成纤维细胞作为神经元的替代物，并且将以多种方式研究MAN-6-P TAG的合成。此外，将用编码酶突变形式的cDNA转染细胞，以遵循对蛋白质折叠，运输，定位和半衰期的潜在影响。总体目标是了解导致口吃的细胞异常。公共卫生相关性：这项研究与分子对涉及溶酶体生物发生的蛋白质中的突变的分子理解直接相关，导致家族性口吃，这是一种相对常见的条件，损害了交流并改变了生命的影响。