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 HS 6-O-Sulfotransferases（HS6STS）中硫酸肝素（HS）6-O-硫酸盐和突变与 多种人脑疾病。但是，这些脑部疾病中HS 6-O-硫化的机制仍然存在 理解不足，当前的疗法受到限制。长期目标是使用鼠标模型来揭示如何 HS 6-O硫化的破坏会影响大脑功能并导致脑部疾病，并希望 最终开发一种治愈方法。该应用的总体目的是揭示 成年小鼠大脑中的星形胶质细胞HS 6-O硫化。中心假设是星形胶质细胞HS 6-O硫化 调节成年小鼠的行为和转录组，并且星形胶质细胞HS 6-O硫化调节星形胶质细胞 通过HS/GPC/FGFR/STAT路径转录组。该项目的理由是确定 体内功能和大脑中HS 6-O硫化的相关机制将提供强大的科学 为这些脑疾病患者开发新疗法的基础。中心假设将通过 追求两个具体的目的：1）确定星形胶质细胞HS 6-O在成年小鼠大脑中的作用；和2） 确定成人星形胶质细胞中HS 6-O硫化的分子机制。该建议具有创新性，因为 它使用新型的突变小鼠系和多学科方法来揭示迄今为止未经证实的过程， HS 6-O-硫化在成年哺乳动物大脑中的作用和机制。预期的结果是1） 提供第一个体内数据，以确定成年人星形细胞HS 6-O-硫化的作用和机制 大脑和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。 拟议的研究很重要，因为它将从根本上提高我们对 HS 6-O硫化及其在大脑中的信号通路，这将有助于我们了解HS 6-O硫化 相关的脑疾病并开发新的疗法。该项目还将提供出色的研究 纽约理工学院代表性不足的少数民族和女学生的机会 （NYIT），并将大大改善NYIT的研究环境。