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Molecular Mechanisms of Intellectual Disability

智力障碍的分子机制

基本信息

批准号：
9104166
负责人：
Ashleigh E Schaffer
金额：
$ 13.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-05 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104166
关键词：
Activities of Daily Living Adult Affect Age Belief Binding Biogenesis Brain Cell Line Cell Survival Cells Clinical Complex Coupled Coupling Deceleration Defect Development Developmental Process Disease Disease Progression Embryo Etiology Failure Family Family member Future Gene Mutation Genes Genetic Genetic Counseling Genetic Transcription Goals Growth Head Health Health Care Costs Human In Vitro Individual Inherited Intellectual functioning disability K-Series Research Career Programs Knowledge Lead Mentors Messenger RNA Microcephaly Modeling Molecular Molecular Analysis Molecular Genetics Monitor Mus Mutate Mutation Nerve Degeneration Neurological Models Neurons Neurophysiology - biologic function Neurosciences Nuclear Export Onset of illness Pathogenesis Pathway interactions Patients Phase Phenotype Phosphotransferases Plant Roots Polyadenylation Pathway Population Process Processed Genes Protein Isoforms Proteins Protocols documentation RNA RNA Processing RNA Splicing RNA immunoprecipitation sequencing Recruitment Activity Research Research Personnel Sequence Analysis Sequencing Biochemistry Site Stem cells Supportive care Techniques Technology Testing Tissues Transcript Yeasts base cell growth clinically relevant exome sequencing human stem cells improved in vivo induced pluripotent stem cell insight loss of function member mutant nerve stem cell nervous system disorder neurodevelopment next generation sequencing novel postnatal prevent relating to nervous system sex stem cell differentiation transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Intellectual disability (ID) is a common untreatable neurological disorder that affects a significant portion of the US population. ID is a major burden to the family as associated health care costs are high and patients with ID are frequently reliant upon family members for their activities of daily living. Little is known about the genetic and molecular mechanisms underlying ID and treatment options are limited to supportive care. One way to improve therapies for ID could be by identifying novel genetic pathways regulating neural development and function. The knowledge gained from these studies will be useful for future development of clinically relevant treatment options for ID patients as well as improve genetic counseling for families. Using whole exome sequencing; I have identified a 3 novel gene mutations in families with inherited progressive microcephaly and ID. These genes encode proteins involved in mRNA processing and nuclear export. Therefore, I hypothesize that mutations in these genes will affect the processing or cellular localization of a subset of mRNAs required for neural viability. To test this hypothesis, I have proposed the following aims: 1. Investigate how mutations in these genes affect neural progenitor cell viability and growth, and maturation of neurons in vitro and in vivo. 2. Determine whether the mutations in these genes alter mRNA splicing, abundance, and cellular localization. 3. Identify direct mRNA targets of these proteins by performing RNA immunoprecipitation and sequencing (RIP-seq). Understanding disease onset and progression as well as the underlying cellular and molecular changes associated with mutations in causal ID genes will provide insight into basic human developmental processes in addition to novel disease mechanisms in patients with ID.

描述（由申请人提供）：智力障碍（ID）是一种常见的无法治疗的神经系统疾病，影响着很大一部分美国人口。身份证是一大负担由于相关的医疗保健费用很高，而且智力障碍患者的日常生活活动经常依赖家庭成员。人们对ID的遗传和分子机制知之甚少，治疗方案仅限于支持性护理。改善智力障碍治疗的一种方法是识别调节神经发育和功能的新遗传途径。从这些研究中获得的知识将有助于未来为智力障碍患者开发临床相关的治疗方案，并改善家庭的遗传咨询。使用全外显子组测序；我在患有遗传性进行性小头畸形和智力障碍的家族中发现了 3 个新的基因突变。这些基因编码参与 mRNA 加工和核输出的蛋白质。因此，我假设这些基因的突变将影响神经活力所需的 mRNA 子集的加工或细胞定位。为了检验这一假设，我提出了以下目标： 1. 研究这些基因的突变如何影响神经祖细胞的活力和生长，以及体外和体内神经元的成熟。 2. 确定这些基因中的突变是否改变 mRNA 剪接、丰度和细胞定位。 3. 通过进行 RNA 免疫沉淀和测序 (RIP-seq) 来识别这些蛋白质的直接 mRNA 靶标。了解疾病的发病和进展以及与 ID 基因突变相关的潜在细胞和分子变化，除了了解 ID 患者的新疾病机制之外，还将深入了解基本的人类发育过程。