Mechanism of disease in TBCK-related intellectual disability syndrome, a novel neurodegenerative disorder with mTOR dysfunction

TBCK相关智力障碍综合征的发病机制，这是一种伴有mTOR功能障碍的新型神经退行性疾病

• 批准号: 9924685
• 负责人: Elizabeth Joyce Bhoj
• 金额: $ 14.31万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924685
• 关键词: 3-Dimensional; Advisory Committees; Affect; Amino Acids; Animal Disease Models; Animal Model; Animals; Antibodies; Autophagocytosis; Behavior; Binding; Biological Markers; Brain; Cells; Cessation of life; Child; Clinical; Clinical Research; Complex; Data; Data Analyses; Defect; Development; Disease; Disease model; Dominant-Negative Mutation; Down-Regulation; Drosophila genus; Drug Screening; Drug Targeting; Early Endosome; Endocytosis; Endocytosis Pathway; Endosomes; Ensure; Evaluation; Experimental Designs; FRAP1 gene; Facies; Family; Fellowship; Fibroblasts; Functional disorder; GTPase-Activating Proteins; Gene Expression; Genes; Genomics; Goals; Grant; Guanosine Triphosphate; Histology; Human; Human Genetics; Impairment; Intellectual functioning disability; International; Intracellular translocation; Involuntary Movements; K-Series Research Career Programs; Knockout Mice; Knowledge; Laboratories; Learning; Leucine; Longevity; Lysosomes; Mediating; Medical Genetics; Mentors; Modeling; Molecular Genetics; Mus; Muscle hypotonia; Mutation; Nerve Degeneration; Nervous system structure; Neuroanatomy; Neurodegenerative Disorders; Neurological Models; Neuromuscular Junction; Neurons; Neurophysiology - biologic function; Neurosciences; Normal Cell; Palliative Care; Pathogenesis; Pathway interactions; Patients; Pattern; Pediatrics; Phenotype; Phosphotransferases; Physicians; Positioning Attribute; Proteins; Publishing; RNA; Reporting; Research; Research Personnel; Residencies; Resources; Role; Scientist; Signal Transduction; Societies; Structure; Syndrome; Techniques; Testing; Therapeutic Agents; Training; Ultrasonics; Up-Regulation; Work; career; disease-causing mutation; experience; experimental study; gain of function; insight; instructor; knock-down; late endosome; member; motor impairment; mouse model; mutant; nervous system disorder; neurodevelopment; neurogenetics; neuromuscular; neuronal growth; neuronal patterning; novel; nursing mothers; pregnant; premature; progressive neurodegeneration; pup; rab5A Protein; relating to nervous system; response; skills; targeted treatment; therapeutic evaluation; therapeutic target; therapy development; tool; vocalization

The training included in this career development award promotes the applicant’s transition to an independent career as an academic neurogeneticist, focused on the mechanisms of novel neurodegenerative disorders. The applicant completed residency training in General Pediatrics and Medical Genetics and fellowship training in Clinical Molecular Genetics, and is now an instructor at CHOP in the Division of Human Genetics. In both her clinical and research work she is dedicated to children with rare neurogenetic disorders. Her short-term goals include developing and refining her skills in animal models of neurologic disorders, and specific wet-bench neuroscience techniques. In addition, she will gain new insight into experimental design, data interpretation, and lab management to ensure her successful transition into leading an academic laboratory in translational neurogenetics. Her co-mentors for the proposal are Drs. Hakon Hakonarson and Zhaolan (Joe) Zhou, international leaders in genomics and neurogenetics. In addition she will be supported by a Scientific Advisory Committee comprised of world leaders in animal models of neurologic disease, neuron structure and function, and translational neurogenetics. She is also strongly supported by outstanding resources of CHOP/Penn, which have a proven track record of successful previous awardees. The applicant recently described a rare neurodegeneration syndrome characterized by hypotonia, developmental regression, and premature death, which resembles a lysosomal storage disorder. Patients with this syndrome have mutations in TBC1 Domain Containing Kinase (TBCK), but little is known about how these mutations cause disease. In addition, there are no animal models of the disease, which has slowed research and targeted therapy development. In patient cells she showed that the mTORC1 pathway is down-regulated in TBCK patients, and that the amino acid leucine may rescue this defect. It also has been reported that TBCK binds RAB5, a vital endosome pathway protein. Therefore, she will test the hypothesis that loss of TBCK leads to dysregulated endosome-lysosome function through RAB5 and mTORC1, which can be treated with leucine. Aim 1 delineates the TBCK-RAB5-mTORC1-endosome pathway in patient cells. These experiments define disease pathogenesis and allow for the identification of additional disease biomarkers and therapeutic targets. Aims 2 and 3 will utilize the first reported animal models of TBCK deficiency, Drosophila and mouse, to delineate its role in the nervous system. She has recently established that both of these models recapitulate the human phenotype. In both models she will quantify behavior, and neuronal growth and patterning. She will then attempt to rescue their phenotypes with leucine. This data will advance our understanding of a novel neurodegeneration mechanism, and possibly advance the first targeted therapy for this progressive and fatal disorder. In addition, this proposal will allow the candidate to gain experience, knowledge, and new skills to successfully launch an independent career as a physician-scientist in neurogenetics.

此职业发展奖中包含的培训促进申请人向职业发展的过渡。 作为一名学术神经遗传学家的独立职业，专注于新的神经退行性疾病的机制， 紊乱申请人完成了普通儿科和医学遗传学的住院医师培训， 在临床分子遗传学的奖学金培训，现在是在CHOP在人类遗传学部讲师 遗传学在她的临床和研究工作中，她致力于患有罕见神经遗传性疾病的儿童。 她的短期目标包括发展和完善她在神经系统疾病动物模型中的技能， 特殊的神经科学技术此外，她将获得实验设计的新见解， 数据解释和实验室管理，以确保她成功过渡到领导学术 翻译神经遗传学实验室她的共同导师的建议是博士Hakon Hakonarson和 Zhaolan（Joe）Zhou，基因组学和神经遗传学的国际领导者。此外，她还将得到以下方面的支持： 一个科学咨询委员会，由神经疾病动物模型、神经元 结构和功能，以及翻译神经遗传学。她还得到了杰出的 CHOP/Penn的资源，这些资源具有成功的往届获奖者的良好记录。 申请人最近描述了一种以张力减退为特征的罕见神经变性综合征， 发育退化和过早死亡，这类似于溶酶体储存障碍。患者 这种综合征在TBC 1含结构域激酶（TBCK）中存在突变，但对这些突变如何发生知之甚少。 突变导致疾病。此外，还没有这种疾病的动物模型，这也减缓了研究的进展 和靶向治疗的发展。在患者细胞中，她发现mTORC 1通路下调， 在TBCK患者中，氨基酸亮氨酸可以挽救这种缺陷。据报道，TBCK 结合RAB 5，一种重要的内体途径蛋白。因此，她将检验TBCK缺失导致 通过RAB 5和mTORC 1调节内体-溶酶体功能失调，这可以用亮氨酸治疗。 目的1描述患者细胞中TBCK-RAB 5-mTORC 1-内体途径。这些实验定义了 疾病的发病机制，并允许鉴定额外的疾病生物标志物和治疗靶点。 目的2和3将利用首次报道的TBCK缺乏症动物模型，果蝇和小鼠， 描述它在神经系统中的作用。她最近发现，这两种模式都概括了 人类的表型在这两个模型中，她将量化行为，神经元的生长和模式。她将 然后尝试用亮氨酸来挽救它们的表型。这些数据将促进我们对小说的理解 神经变性机制，并可能推进这种进行性和致命的第一个靶向治疗 disorder.此外，该提案将使候选人获得经验，知识和新技能， 成功地开始了一个独立的职业生涯，作为一个医生，科学家在神经遗传学。