Genetics of Adult Idiopathic Hydrocephalus

成人特发性脑积水的遗传学

基本信息

批准号：
10354856
负责人：
MARK D JOHNSON
金额：
$ 3.2万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354856
关键词：
Adult Affect Age Aging Alzheimer&apos s Disease American Autopsy Blood Cell Count Cell physiology Cells Cerebral Ventricles Cerebrospinal Fluid Cerebrum Cilia Congenital Hydrocephalus DNA Sequence Alteration Dementia Dependence Development Diagnosis Disease Drainage procedure Ependyma Ependymal Cell Epithelial Etiology Family history of Fecal Incontinence Frequencies Functional disorder Gait Gene Expression Genes Genetic Genotype Goals Health Personnel Healthcare Human Hydrocephalus Impairment In Vitro Incontinence Knockout Mice Lead Length Mediating Mus Mutagenesis Mutate Mutation Neurodegenerative Disorders Normal Pressure Hydrocephalus Nursing Homes Parkinson Disease Patients Phenotype Proteins RXFP2 gene Recurrence Reporting Role Shunt Device Signs and Symptoms Small Interfering RNA Specimen Structure Structure of choroid plexus Symptoms Techniques Testing Ventricular Walking Wild Type Mouse accurate diagnosis age related base cardiovascular risk factor cilium motility exome sequencing human old age (65+)improved in vivo knock-down loss of function mouse model nervous system disorder protein function protein structure urinary

项目摘要

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence and dementia. It is a common disorder that occurs almost exclusively after the age of 60. About 1.3% of patients over the age of 65 and 9-14% of nursing home residents are thought to have iNPH. Unfortunately, more than 90% of these patients remain misdiagnosed or undiagnosed, in part because the symptoms of iNPH resemble the symptoms of other neurodegenerative diseases, and in part because many health care practitioners are unfamiliar with this disorder. The etiology of iNPH is not known. Scattered reports of familial cases of iNPH suggest a genetic origin, but the genes involved are unknown. To investigate this matter, we have used exome sequencing to look for genetic factors associated with iNPH. We find recurrent heterozygous mutations in 10 genes, nearly all of which show increased expression in the ciliated ventricular epithelium and/or choroid plexus. Many have previously been associated with the function of cilia. siRNA-mediated knockdown of several of these genes increased ventricular size in vivo, and knockdown of one of these was also shown to decrease cilia number and length in vivo. Importantly, we and others find that ventricular volume increases with age in humans and in mice, and we observed that cilia number and length decreases with age in mice. This proposal will use whole exome sequencing and in vitro and in vivo mouse models to test the hypothesis that heterozygous mutations that compromise the function of motile cilia, combined with age-related declines in ciliated ependymal cell function, lead to iNPH. If successful, the findings may lead to improved understanding, diagnosis or treatment of iNPH.

特发性正常压力脑积水（INPH）是一种衰老的神经系统障碍通过脑室的扩大，步态难度，失禁和痴呆症。这是一种常见的疾病几乎完全发生在60岁之后。大约1.3％的患者65岁和9-14％养老院居民被认为有INPH。不幸的是，这些患者中有90％以上保持误诊或未诊断，部分是因为INPH的症状类似于其他神经退行性疾病，部分原因是许多医疗保健从业者不熟悉有这种疾病。 INPH的病因尚不清楚。家族案例的分散报告表明遗传来源，但所涉及的基因尚不清楚。为了调查此事，我们已经使用了外显子公司测序以寻找与INPH相关的遗传因素。我们发现在 10个基因，几乎所有基因在纤毛的心室上皮和/或脉络丛。许多以前与纤毛的功能有关。 siRNA介导的这些基因中的几个基因的敲低增加了体内的心室大小，其中一个敲低还显示体内减少纤毛数和长度。重要的是，我们和其他人发现人类和小鼠的心室体积随着年龄的增长而增加，我们观察到纤毛数量和小鼠的长度随着年龄的增长而降低。该建议将使用整个外显子组测序，体外和体内小鼠模型以检验以下假设： Motile纤毛与年龄相关的纤毛膜室室功能下降，导致INPH。如果成功，发现可能会导致对INPH的理解，诊断或治疗的改善。