Bernadette Holdener, PhD
2019 Innovator Award Recipient
TITLE: Associate Professor, Stony Brook University
GOAL: Understanding how disturbances in the way the brain produces and uses energy are related to the development of hydrocephalus in both children and adults.
We identified a new mouse mutation that links hydrocephalus to a missing sugar modification on proteins that share a motif called a ThromboSpondin type I Repeat (TSR). The B3GLCT enzyme adds glucose onto the TSRs of forty-nine extracellular matrix or membrane linked proteins, and 50% of B3glct mutants develop hydrocephalus. The goals of the proposed research are to identify the cause of hydrocephalus in B3glct mutants, and identify the B3GLCT-modified proteins impacted by loss of the glucose modification. Because B3GLCT utilizes UDP-glucose to modify the target proteins, we predict that defects in glucose metabolism or UDP-glucose synthesis/transport could also contribute to the development of hydrocephalus (both developmental and adult onset) by interfering with B3GLCT-modified protein function. Results from the proposed studies will provide a baseline for future studies that will investigate the impact of metabolic defects on the penetrance of hydrocephalus in B3glct mutants and on the function of the B3GLCT-modified targets.