Astrocytic Heparan Sulfate 6-O-Sulfation in Brain Function

摘要 硫酸乙酰肝素(HS)6-O-磺化和HS 6-O-磺基转移酶(HS6STs)突变与 人类多发性脑部疾病。然而，HS6-O-硫化在这些脑部疾病中的作用机制仍然存在 人们对此知之甚少，目前的治疗方法有限。长期目标是使用老鼠模型来揭示 HS 6-O-硫酸盐的破坏会影响大脑功能，并导致大脑紊乱，希望能 最终开发出一种治疗方法。本应用程序的总体目标是揭示 成年小鼠脑内的星形细胞HS 6-O-硫酸盐。中心假设是星形细胞的HS6-O-硫酸盐 调节成年小鼠的行为和转录组，星形胶质细胞的HS6-O-硫酸盐调节星形胶质细胞 转录组通过HS/GPC/FGFR/Stat途径。该项目的基本原理是确定在 HS6-O-硫酸盐在脑内的体内功能及其相关机制将为研究提供强有力的科学依据 为这些大脑疾病患者开发新的治疗方法奠定了基础。核心假设将通过以下方式进行检验 追求两个具体目标：1)确定星形细胞HS6-O-硫酸盐在成年小鼠脑中的作用；2) 鉴定成年星形胶质细胞HS6-O-硫酸盐化的分子机制。这项建议具有创新性，因为 它使用新的突变小鼠品系和多学科方法来揭示一个迄今未被研究的过程， HS 6-O-硫化在成年哺乳动物脑中的作用和机制。预期结果为1)至 首次提供体内数据以确定星形胶质细胞HS 6-O-硫酸盐在成人中的作用和机制 2)揭示成年星形胶质细胞HS/GPC/FGFR/STAT信号通路的详细机制。 这项拟议的研究具有重要意义，因为它将从根本上促进我们对 HS6-O-硫化及其在脑内的信号通路有助于我们理解HS6-O-硫化 相关的大脑疾病，并开发新的治疗方法。该项目还将提供出色的研究 纽约理工学院代表不足的少数族裔和女学生的机会 (NYIT)，并将显著改善NYIT的研究环境。

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.