Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

常染色体隐性神经疾病的遗传学和功能研究

基本信息

批准号：
9923765
负责人：
Saima Riazuddin
金额：
$ 59万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923765
关键词：
Adaptive Behaviors Address Affect Alleles Antibodies Bioinformatics Biological Assay Brain Brain region Cells Cellular Morphology Clinical Clinical assessments Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Critical Pathways Data Development Diagnosis Diagnostic Disability phenotype Disease Economic Burden Electrophysiology (science)Electroporation Emotional Etiology Extended Family Family Family Sizes Family member Financial Hardship Functional disorder Gene Proteins Genes Genetic Genetic Counseling Genomics Goals Health Healthcare Systems High Prevalence Hippocampus (Brain)Human Impaired cognition Impairment Inbreeding Individual Inhibitor of Differentiation Proteins Intellectual functioning disability Knowledge Lead Lesion Lod Score Medical Methods Mission Molecular Molecular Biology Molecular Diagnosis Molecular Genetics Mus Mutate Neurodevelopmental Disorder Neurologic Neurons Pakistan Parietal Pathogenesis Pathogenicity Pathway interactions Pattern Phenotype Population Heterogeneity Positioning Attribute Prevalence Prevention Preventive Protein Family Proteins Rattus Reagent Reporting Research Risk Rodent Role SNP genotyping Sampling Scanning Societies Specific qualifier value Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Agents United States National Institutes of Health Variant X Chromosome autism spectrum disorder burden of illness care costs clinical phenotype clinically relevant cognitive function cohort consanguineous family exome sequencing gene function gene product genetic pedigree genetic variant genome editing genome sequencing genome-wide human disease improved in utero in vivo life time cost live cell imaging member mutant nervous system disorder neural circuit neurotransmission new therapeutic target novel novel therapeutics outcome forecast protein structure research clinical testing screening simulation skills social socioeconomics spatiotemporal subcellular targeting synaptic function targeted treatment tool whole genome

项目摘要

Project Summary According to WHO estimates, neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. It is manifested by deficits in adaptive behaviors in everyday social and practical skills, which can have a devastating effect on the lives of affected individuals and their families. Due to its high prevalence of 2-3%,2; 3 and the lifetime cost of care per individual in the range of $1-2 million in United Sates,4 ID presents a significant health burden and is a major challenge at the clinical level. Genetic factors are involved in the etiology of 25-50% of ID cases. 2 Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However the identity of a large number of essential molecular and cellular components remain unknown. The Objective of the proposed research is to identify and characterize genes/proteins essential for autosomal recessive ID (ARID). The rationale is that identification of causative gene variants that lead to ARID and elucidation of the functions of normal genes will be essential for understanding brain function and developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders in general and ID in particular. The project addresses NIH’s mission to generate basic knowledge that may be translatable to reduce the burden of human diseases. There are 3 aims: 1) Ascertain and clinically phenotype members of extended families segregating ARID; 2) identify new ARID genes and gene products; and 3) determine synaptic functions of prioritized novel ARID genes, by analyzing spatiotemporal expression patterns in mouse brain, synaptic targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology, live-cell imaging, and in utero electroporation assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutics targets to slow progression, delay onset, and possibly treat some forms of ID.

项目概要据世界卫生组织估计，神经系统疾病占全球疾病负担的 6% 以上。超过 600 种神经系统疾病和认知功能障碍，也称为智力障碍 (ID)，在此列表中占据突出位置，表现为日常社交和适应行为的缺陷。实际技能可能会对受影响个人及其家人的生活产生毁灭性影响。其患病率高达 2-3%2；3 并且美国每人的终生护理费用在 1-200 万美元之间 Sates，4 ID 带来了重大的健康负担，并且是临床层面的主要挑战。涉及 25-50% ID 病例的病因学 2 基因和蛋白质的遗传和功能研究。 ID 的决定因素有助于阐明人类大脑在健康和健康方面发育的分子途径。然而，大量重要分子和细胞成分的身份仍然存在未知拟议研究的目的是识别和表征必需的基因/蛋白质。常染色体隐性遗传 ID (ARID) 的基本原理是识别导致 ARID 的致病基因变异。阐明正常基因的功能对于理解大脑功能和发育至关重要改善一般神经系统疾病的诊断工具和有效的预防和治疗药物该项目特别强调 NIH 的使命，即生成可翻译的基础知识。减轻人类疾病负担有 3 个目标：1）确定成员并确定其临床表型。分离 ARID 的大家族；2) 识别新的 ARID 基因和基因产物；3) 确定突触；通过分析小鼠大脑中的时空表达模式，确定优先新颖的 ARID 基因的功能，培养的大鼠海马神经元的突触靶向，对细胞形态和突触丰度的影响，通过电生理学、活细胞成像和子宫内神经元细胞的突触传递和可塑性该项目将有利地结合人类临床评估、遗传和与大脑发育和功能相关的功能分析：执行拟议的研究将。产生与临床相关的新知识，很有可能影响 ID 分子诊断，预测，并确定新的治疗目标，以减缓进展、延迟发病，并可能治疗某些疾病身份证明的形式。