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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.

项目总结