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

该职业发展奖中包括的培训将促进申请者过渡到 作为学术神经遗传学家的独立职业生涯，专注于新型神经退行性疾病的机制 精神错乱。申请人完成了普通儿科和医学遗传学的住院医师培训，并 临床分子遗传学研究员培训，现为人类基因组学分部CHOP讲师 遗传学。在她的临床和研究工作中，她致力于治疗患有罕见神经遗传疾病的儿童。 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，以及 特殊的湿板凳神经科学技术。此外，她还将对实验设计有新的见解， 数据解释和实验室管理，以确保她成功过渡到领先的学者 翻译神经遗传学实验室。她的提议的共同导师是Hakon Hakonarson博士和 周兆兰，基因组学和神经遗传学的国际领先者。此外，她还将得到 由神经疾病动物模型、神经元的世界领先者组成的科学咨询委员会 结构和功能，以及翻译神经遗传学。她也得到了杰出人士的大力支持 CHOP/宾夕法尼亚大学的资源，他们有成功的前获奖者的良好记录。 申请人最近描述了一种罕见的神经变性综合征，其特征是低张力， 发育退化和过早死亡，这类似于溶酶体储存障碍。患有疾病的患者 这种综合征在含TBC1域的激酶(TBCK)上有突变，但对这些突变的原因知之甚少 突变会导致疾病。此外，目前还没有这种疾病的动物模型，这减缓了研究的速度 和靶向治疗的发展。在患者细胞中，她发现mTORC1途径被下调 在TBCK患者中，氨基酸亮氨酸可以挽救这一缺陷。另有报道称，TBCK 与RAB5结合，RAB5是一种重要的内容体途径蛋白。因此，她将检验失去TBCK领先的假设 通过RAB5和mTORC1调节内体-溶酶体功能紊乱，亮氨酸可对其进行治疗。 目的1研究患者细胞中的TBCK-RAB5-mTORC1-内切酶途径。这些实验定义了 疾病的发病机制，并允许确定其他疾病的生物标志物和治疗目标。 AIMS 2和3将利用首次报道的TBCK缺乏症动物模型--果蝇和小鼠--来 描述它在神经系统中的作用。她最近证实，这两个模型都概括了 人类的表型。在这两个模型中，她将量化行为以及神经元的生长和模式。她会的 然后尝试用亮氨酸挽救它们的表型。这些数据将促进我们对小说的理解 神经退行性变的机制，并可能推进这种进行性和致命性的首个靶向治疗 无序。此外，这项建议将使应聘者获得经验、知识和新技能，以 成功地开创了独立的职业生涯，成为神经遗传学的内科科学家。

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.