Bhoj Lab Research Overview

Thousands of children are suspected to have a genetic disorder but have no diagnosis, even after expert evaluation. Many of these children have yet-undiscovered genetic syndromes, and the Bhoj Lab aims to provide answers to families about their child's medical issues and work toward targeted therapies for genetic disorders. The lab uses advanced sequencing technology to identify these novel syndromes. Two of the syndromes focused on in the lab are caused by disruption of Histone 3.3 (H3F3A and H3F3B) and TBC1 domain-containing Kinase (TBCK).

Histone 3.3 is a replacement histone, and is vital for appropriate cell division, transcription, and many other processes. Somatic variants cause a variety of cancer, including pediatric glioblastoma. The Bhoj Lab described a pediatric neurodegenerative condition caused by germline variants in H3F3A and H3F3B, which both code for Histone 3.3. Using patient cells, mouse models, and iPSC cells, the lab team is learning more about why these genetic variants cause this disease. Their goal is to be able to learn enough about the pathogenesis of the disorder to develop the first targeted therapies for this progressive neurologic disorder.In addition, the lab was instrumental in the discovery of TBC1 domain-containing Kinase (TBCK) as a cause of progressive neurodegeneration in children. Little is known about TBCK, and the lab is learning more about how TBCK works in healthy tissues and contributes to neurodegeneration. The team uses patient cells and model organisms to understand how the loss of this protein disrupts normal neurologic development. Early data suggested the mTOR pathway was downregulated in these patients, and the Bhoj Lab showed that leucine, an amino acid, is a potential targeted therapy. The lab is now working on leucine and related compounds in animal models of the disease with the aim of starting a human trial.

Project Highlights

• Novel human gene discovery in pediatric patients with undiagnosed syndromes
• Pathogenesis and therapy development in patients with Histone 3.3-related neurologic dysfunction — both animal models and human cells.
• Role of TBCK in normal and abnormal neurodevelopment, leucine and related compounds to treat TBCK-related neurodegeneration.
• The mechanism of MAP4K4, a novel RASopathy gene, in neurologic and psychiatric disease. Pathway analysis and drug screen for targeted therapies.