Genetics of Adult Idiopathic Hydrocephalus

成人特发性脑积水的遗传学

• 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
• 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' 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

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) 是一种衰老性神经系统疾病，其特征是 脑室扩大、步态困难、失禁和痴呆。这是一种常见的疾病 几乎全部发生在 60 岁以后。大约 1.3% 的患者年龄超过 65 岁，9-14% 的患者 疗养院居民被认为患有 INPH。不幸的是，超过 90% 的患者 仍然被误诊或未确诊，部分原因是 iNPH 的症状与 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 患有这种疾病。 iNPH 的病因尚不清楚。 iNPH 家族病例的零星报告表明 遗传起源，但所涉及的基因尚不清楚。为了研究这个问题，我们使用了外显子组 测序寻找与 iNPH 相关的遗传因素。我们发现反复出现的杂合突变 10 个基因，几乎所有这些基因在纤毛心室上皮和/或 脉络丛。许多先前已被认为与纤毛的功能有关。 siRNA介导的 敲低这些基因中的几个会增加体内心室的大小，敲除其中一个基因会增加体内心室的大小 还被证明可以减少体内纤毛的数量和长度。重要的是，我们和其他人发现 在人类和小鼠中，心室容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减小。该提案将使用全外显子组测序以及体外和体内测序 体内小鼠模型来测试杂合突变损害功能的假设 运动纤毛，加上与年龄相关的纤毛室管膜细胞功能下降，导致 iNPH。如果 如果成功的话，研究结果可能会提高对 iNPH 的理解、诊断或治疗。