Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction.

膀胱功能障碍的新单基因原因的发现和致病特征。

• 批准号: 10381698
• 负责人: Nina Mann
• 金额: $ 16.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381698
• 关键词: Adult; Advisory Committees; Affect; Anatomy; Animal Model; Autonomic nervous system; Behavior; Behavioral; Bladder; Bladder Dysfunction; Boston; Candidate Disease Gene; Child; Childhood; Chronic Kidney Failure; Copy Number Polymorphism; Data; Defect; Development; Development Plans; Disease; End stage renal failure; Ensure; Environment; Etiology; Gene Expression; Genes; Genetic; Genets; Genitourinary system; Genomic approach; Genomics; Grant; Healthcare; Human; Impairment; Individual; International; Kidney; Laboratories; Lead; Life; Lower urinary tract; Mediating; Mentors; Mesenchyme; Metanephric Diverticulum; Methods; Microarray Analysis; Molecular; Muscle Contraction; Muscle relaxation phase; Mutation; Nervous System Physiology; Neurogenic Bladder; Neurologic Deficit; Nicotinic Receptors; Obstruction; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric Hospitals; Population; Proteins; RNA Splicing; Regulation; Relaxation; Renal Replacement Therapy; Reporting; Research; Research Personnel; Signal Transduction; Smooth Muscle; Specimen; Syndrome; Techniques; Therapeutic; Therapeutic Intervention; Training; Urinary tract; Urine; Urologic Diseases; Urothelium; Validation; Variant; base; care burden; career development; cohort; congenital anomalies of the kidney; diagnostic value; exome; exome sequencing; genetic disorder diagnosis; genetic pedigree; genetic variant; human disease; insight; malformation; medical schools; meetings; nephrogenesis; nerve supply; novel; novel therapeutic intervention; prenatal; prevent; research and development; success; symposium; transcriptome sequencing; transcriptomics; urinary; urinary tract obstruction

PROJECT SUMMARY Title: Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood. Over 40 monogenic etiologies of CAKUT have been identified, and another 150 genes have been described to cause syndromes in which urinary tract malformations are an integral component. However, the majority of these genes coalesce into pathways that regulate upper urinary tract development, such as metanephric mesenchyme transition and ureteric bud formation. The pathogenesis and genetic regulation of lower urinary tract disease remain poorly understood. Recently, through the use of whole exome sequencing, I identified mutations in the α3-subunit of the nicotinic acetylcholine receptor, CHRNA3, as a novel cause of bladder dysfunction with secondary CAKUT. This is one of just eight known monogenic causes of congenital bladder dysfunction, and, uniquely, is a gene that regulates autonomic nervous system function. I hypothesize that additional monogenic causes of lower urinary tract disease can be identified through the use of whole exome sequencing, and additionally, that these genes will coalesce upon pathways that regulate urothelial signaling, detrusor contraction, and bladder innervation. The aims of the proposed research are twofold: (1) to apply both a candidate gene and unbiased analysis strategy to whole exome sequencing data in order to discover novel monogenic causes of bladder dysfunction and (2) to apply an integrated genomic approach using whole exome and whole transcriptome sequencing to an international cohort of children with CAKUT. Accomplishment of the proposed research above will provide additional insight into the pathomechanisms that govern bladder development and function, and, ultimately, could lead to novel therapeutic strategies for children with bladder dysfunction. In addition, validation of a method for urinary transcriptome sequencing can help to overcome current limitations in whole exome sequencing in the identification and interpretation of splice-altering genetic variants. This K08 application encompasses a comprehensive career development plan to not only ensure progress and success in carrying out the proposed research, but also to facilitate my transition to an independent investigator. It encompasses regular meetings with my mentor and advisory committee, research and career development seminars, courses in genomics and transcriptomics, and participation at national and international conferences. The research will be conducted in the rich academic environment at Boston Children's Hospital and Harvard Medical School, which provides an ideal environment for further training and career development.

项目摘要 标题：膀胱功能障碍的新型单基因原因的发现和病原学特征 先天性肾脏和泌尿道异常（CAKUT）是慢性肾功能衰竭最常见的原因。 儿童期肾病CAKUT的单基因病因已经确定了40多个，另外150个 基因已经被描述为引起综合征，其中泌尿道畸形是综合征的组成部分， 成分然而，这些基因中的大多数结合成调节上尿路的通路， 后肾间充质的转变和输尿管芽的形成。发病机制及 下尿路疾病的遗传调控仍然知之甚少。最近，通过使用整个 通过外显子组测序，我确定了烟碱乙酰胆碱受体α3亚基CHRNA3的突变， 继发性CAKUT的膀胱功能障碍的新原因。这是已知的八个单基因 先天性膀胱功能障碍的原因，而且，独特的是，是一个基因，调节自主神经系统 功能我假设可以确定下尿路疾病的其他单基因原因 通过使用整个外显子组测序，此外，这些基因将结合在 调节尿路上皮信号传导、逼尿肌收缩和膀胱神经支配的途径。 本研究的目的有二：（1）应用候选基因和无偏分析 全外显子组测序数据的策略，以发现膀胱功能障碍的新单基因原因 和（2）应用使用全外显子组和全转录组测序的整合基因组方法， 一个CAKUT儿童的国际队列。上述研究成果的完成，将为 对支配膀胱发育和功能的病理机制的额外洞察，并且，最终， 可能为膀胱功能障碍儿童带来新的治疗策略。此外，验证a 尿转录组测序的方法可以帮助克服目前在整个外显子组中的限制 测序在识别和解释剪接改变的遗传变异。 此K08应用程序包含一个全面的职业发展计划，不仅确保进步 并成功地进行了拟议的研究，但也有利于我过渡到一个独立的 调查员它包括与我的导师和咨询委员会定期会议，研究和职业生涯 发展研讨会，基因组学和转录组学课程，以及参加国家和 个国际性会议这项研究将在波士顿丰富的学术环境中进行 儿童医院和哈佛医学院，为进一步培训和 职业发展。