# Mechanism of disease in TBCK-related intellectual disability syndrome, a novel neurodegenerative disorder with mTOR dysfunction > **NIH NIH K08** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $143,095 ## Abstract 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 ... ## Key facts - **NIH application ID:** 10137327 - **Project number:** 5K08NS109281-03 - **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA - **Principal Investigator:** Elizabeth Joyce Bhoj - **Activity code:** K08 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $143,095 - **Award type:** 5 - **Project period:** 2019-05-01 → 2022-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10137327 ## Citation > US National Institutes of Health, RePORTER application 10137327, Mechanism of disease in TBCK-related intellectual disability syndrome, a novel neurodegenerative disorder with mTOR dysfunction (5K08NS109281-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137327. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*