Astrocytic Heparan Sulfate 6-O-Sulfation in Brain Function

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ABSTRACT Heparan sulfate (HS) 6-O-sulfation and mutations in the HS 6-O-sulfotransferases (HS6STs) are linked to multiple human brain disorders. However, the mechanisms of HS 6-O-sulfation in these brain disorders remain poorly understood, and current therapies are limited. The long-term goal is to use mouse models to reveal how disruptions of HS 6-O-sulfation affect brain functions and contribute to brain disorders, with a hope to eventually develop a cure. The overall objective of this application is to reveal the role and mechanisms of astrocytic HS 6-O-sulfation in the adult mouse brain. The central hypothesis is that astrocytic HS 6-O-sulfation regulates behavior and transcriptome in adult mice, and that astrocytic HS 6-O-sulfation regulates astrocyte transcriptome via the HS/Gpc/Fgfr/Stat pathway. The rationale for this project is that a determination of the in vivo functions and the associated mechanisms of HS 6-O-sulfation in the brain will offer a strong scientific basis to develop new therapies for patients with these brain disorders. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the role of astrocytic HS 6-O-sulfation in adult mouse brain; and 2) Identify the molecular mechanisms of HS 6-O-sulfation in adult astrocytes. This proposal is innovative because it uses novel mutant mouse lines and multidisciplinary approaches to reveal a heretofore-unexamined process, the role and mechanisms of HS 6-O-sulfation in the adult mammalian brain. The expected outcomes are 1) to provide the first in vivo data to determine the role and mechanisms of astrocytic HS 6-O-sulfation in the adult brain and 2) to reveal the detailed mechanisms of the HS/Gpc/Fgfr/Stat signaling pathway in adult astrocytes. The proposed research is significant because it will fundamentally advance our mechanistic understanding of HS 6-O-sulfation and its signaling pathways in the brain, which will help us to understand HS 6-O-sulfation associated brain disorders and to develop novel therapies. This project will also provide excellent research opportunities for the underrepresented minority and female students at the New York Institute of Technology (NYIT) and will significantly enhance the research environment at NYIT.