Astrocytic Heparan Sulfate 6-O-Sulfation in Brain Function

星形细胞硫酸乙酰肝素 6-O-硫酸化对脑功能的影响

• 批准号: 10578904
• 负责人: Yingtao Zhao
• 金额: $ 42.84万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578904
• 关键词: Adult; Affect; Alzheimer' s Disease; Anions; Astrocytes; Behavior; Behavioral; Binding; Biochemical; Bioinformatics; Biological Assay; Brain; Brain Diseases; Cells; ChIP-seq; Chromatin; Cytoplasm; Data; Dependovirus; Development; Ectopic Expression; Embryo; Environment; FGF5 gene; FGFR3 gene; Female; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Glycosaminoglycans; Glypican; Goals; Gonadotropin Hormone Releasing Hormone; Heparitin Sulfate; High Pressure Liquid Chromatography; Hippocampus; Human; Injections; Intellectual functioning disability; Kallmann Syndrome; Knock-out; Link; LoxP-flanked allele; Measures; Memory; Memory impairment; Modification; Molecular; Mus; Mutant Strains Mice; Mutation; Neuroglia; Neurons; New York; Outcome; Pathway interactions; Patients; Pharmacological Treatment; Process; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stat3 Signaling Pathway; Students; Sulfate; Surface; Tamoxifen; Technology; Testing; Tissues; Transposase; Underrepresented Minority; Work; autism spectrum disorder; behavior test; cell type; extracellular; hormone deficiency; in vivo; innovation; interdisciplinary approach; knock-down; mouse model; novel; novel therapeutics; selective expression; sulfotransferase; transcription factor; transcriptome; transcriptome sequencing

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.

抽象的 硫酸乙酰肝素 (HS) 6-O-硫酸化和 HS 6-O-磺基转移酶 (HS6ST) 的突变与 多种人类大脑疾病。然而，HS 6-O-硫酸化在这些脑部疾病中的机制仍然存在 人们对此知之甚少，目前的治疗方法也很有限。长期目标是使用小鼠模型来揭示如何 HS 6-O-硫酸化的破坏会影响大脑功能并导致大脑疾病，希望能够 最终开发出治疗方法。该应用程序的总体目标是揭示 成年小鼠大脑中星形胶质细胞 HS 6-O-硫酸化。中心假设是星形胶质细胞 HS 6-O-硫酸化 调节成年小鼠的行为和转录组，星形胶质细胞 HS 6-O-硫酸化调节星形胶质细胞 通过 HS/Gpc/Fgfr/Stat 途径转录组。该项目的基本原理是确定 大脑中 HS 6-O-硫酸化的体内功能和相关机制将为我们提供强有力的科学依据。 为患有这些脑部疾病的患者开发新疗法奠定了基础。中心假设将被检验 追求两个具体目标：1) 确定星形胶质细胞 HS 6-O-硫酸化在成年小鼠大脑中的作用；和 2) 确定成年星形胶质细胞中 HS 6-O-硫酸化的分子机制。这个提议之所以具有创新性是因为 它使用新颖的突变小鼠系和多学科方法来揭示迄今为止未经检验的过程， HS 6-O-硫酸化在成年哺乳动物大脑中的作用和机制。预期结果是 1) 到 提供第一个体内数据以确定星形胶质细胞 HS 6-O-硫酸化在成人中的作用和机制 2）揭示成人星形胶质细胞中 HS/Gpc/Fgfr/Stat 信号通路的详细机制。 拟议的研究意义重大，因为它将从根本上推进我们对 HS 6-O-硫酸化及其在大脑中的信号通路，这将有助于我们了解HS 6-O-硫酸化 相关的脑部疾病并开发新的疗法。该项目还将提供出色的研究 纽约理工学院为少数族裔和女学生提供的机会 （纽约理工学院）并将显着改善纽约理工学院的研究环境。