Genetic study of heparan sulfate function in development

硫酸乙酰肝素发育功能的遗传学研究

• 批准号: 7905952
• 负责人: Hiroshi Nakato
• 金额: $ 27.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-29 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905952
• 关键词: Anabolism; Animal Model; Biochemical; Biological; Biological Models; Biological Process; Biology; Cell Differentiation process; Cell Maintenance; Cell surface; Cells; Characteristics; Complex; Cues; Data; Development; Developmental Process; Drosophila genus; Drosophila melanogaster; Enzymes; Event; Family; Fibroblast Growth Factor; Financial compensation; Genes; Genetic; Glypican; Goals; Growth Factor; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hereditary Disease; Human Genetics; In Vitro; Inorganic Sulfates; Janus kinase; Life; Ligands; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Oogenesis; Organism; Ovary; Pathway interactions; Pattern; Phenotype; Play; Proteins; Proteoglycan; Research; Role; STAT protein; Signal Transduction; Somatic Cell; Specificity; Stem cells; Structure; System; Time; Unspecified or Sulfate Ion Sulfates; Wing; axon guidance; base; cationic antimicrobial protein CAP 37; epimerase; flexibility; in vivo; insight; member; morphogens; mutant; novel; public health relevance; research study; stem cell niche; sulfation; sulfotransferase; tool; Anabolism; Animal Model; Biochemical; Biological; Biological Models; Biological Process; Biology; Cell Differentiation process; Cell Maintenance; Cell surface; Cells; Characteristics; Complex; Cues; Data; Development; Developmental Process; Drosophila genus; Drosophila melanogaster; Enzymes; Event; Family; Fibroblast Growth Factor; Financial compensation; Genes; Genetic; Glypican; Goals; Growth Factor; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Hereditary Disease; Human Genetics; In Vitro; Inorganic Sulfates; Janus kinase; Life; Ligands; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Oogenesis; Organism; Ovary; Pathway interactions; Pattern; Phenotype; Play; Proteins; Proteoglycan; Research; Role; STAT protein; Signal Transduction; Somatic Cell; Specificity; Stem cells; Structure; System; Time; Unspecified or Sulfate Ion Sulfates; Wing; axon guidance; base; cationic antimicrobial protein CAP 37; epimerase; flexibility; in vivo; insight; member; morphogens; mutant; novel; public health relevance; research study; stem cell niche; sulfation; sulfotransferase; tool

DESCRIPTION (provided by applicant): Genetic studies have demonstrated that heparan sulfate proteoglycans (HSPGs) are essential for reception of growth factors on the cell surface, formation of morphogen gradients, and axon guidance. HSPGs function in many different biological contexts, yet very little is known about the molecular basis for their activities. We are using the genetic tools available in Drosophila to investigate several outstanding questions in proteoglycan biology, including mechanisms regulating HSPG function and new developmental roles for HSPGs. One important yet unsolved question is how the specificity of HSPG functions for different ligand proteins is generated. HS chains have markedly heterogeneous structures produced by the regulated introduction of N-, 2-O-, 6-O-, and 3-O-sulfate groups. Evidence suggests that these "fine structures" of HS control discrete signaling events at the cell surface. The molecular mechanisms for this control, however, are largely unknown. One of our goals is to understand how specific HS fine structures are generated and function in vivo during development. Another goal of our research is to identify and explore novel roles of HSPGs in development. We previously found that HSPGs regulate the gradient formation of morphogens in the developmental field. We now propose a new model that HSPGs are also involved in the formation of the stem cell niche, another developmental process where cells receive positional cues in a strictly controlled fashion. Our preliminary study strongly suggests that HSPGs are required for the establishment of the germline stem cell (GSC) niche in the developing ovary through a different mode of action from their activity in the developing wing. We propose to elucidate the molecular mechanisms by which HSPGs regulate the formation of the Drosophila GSC niche. Our study also aims to identify novel HS-dependent signaling. Our preliminary data indicate that Drosophila HSPGs participate in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in the ovary. The involvement of HSPGs in this pathway has never been demonstrated in any model system to date, although Unpaired, a known ligand of the Drosophila JAK/STAT pathway, is a heparin binding protein. We will investigate the roles of HSPGs in this pathway using Drosophila oogenesis as our model. Our specific aims of the proposed research are: Aim 1. Explore the molecular functions of HS modifying enzymes in signaling during Drosophila development. Aim 2. Explore roles of HSPGs in Drosophila germline stem cell niche. Aim 3. Establish roles of HSPGs in the JAK/STAT pathway. PUBLIC HEALTH RELEVANCE: Heparan sulfate proteoglycans (HSPGs) are involved in a variety of biological processes such as growth factor signaling, morphogen gradient formation, and axon guidance. Disruption of normal HSPG biosynthesis leads to many human genetic diseases as well as cancer formation. The long term goal of this study is to understand the molecular basis for the function and biosynthesis of HSPGs during development using a genetically tractable model organism, Drosophila melanogaster.

描述（由申请人提供）：遗传研究表明，硫酸乙酰肝素蛋白聚糖（HSPG）对于接收细胞表面生长因子，形成形成梯度和轴突指导至关重要。 HSPG在许多不同的生物学环境中起作用，但对其活性的分子基础知之甚少。我们正在使用果蝇中可用的遗传工具来研究蛋白聚糖生物学中的几个杰出问题，包括调节HSPG功能的机制和HSPG的新发育作用。一个重要但未解决的问题是如何生成HSPG功能对不同配体蛋白的特异性。 HS链的链条显着异质结构，该结构由受调节的N-，2-O-，6-O-和3-O-硫酸盐组产生。有证据表明，HS的这些“精细结构”控制细胞表面的离散信号传导事件。但是，该对照的分子机制在很大程度上尚不清楚。我们的目标之一是了解如何在开发过程中生成特定的HS细胞结构并在体内发挥作用。我们研究的另一个目标是识别和探索HSPG在开发中的新作用。我们先前发现HSPG调节发育领域中形态的梯度形成。现在，我们提出了一种新模型，即HSPG也参与了干细胞生态位的形成，这是另一个开发过程，在该过程中，细胞以严格控制的方式接收位置提示。我们的初步研究强烈地表明，通过与发育中的活性不同的活动方式，在发育中的卵巢中建立种系干细胞（GSC）生态裂市场所必需的HSPG是必需的。我们建议阐明HSPG调节果蝇GSC构成形成的分子机制。我们的研究还旨在鉴定新型HS依赖性信号传导。我们的初步数据表明，果蝇HSPG参与了卵巢中的Janus激酶/信号换能器和转录激活因子（JAK/STAT）途径。迄今为止，在任何模型系统中，HSPG中的参与从未在该途径中得到证明，尽管未配对的果蝇JAK/Stat途径的已知配体是一种肝素结合蛋白。我们将使用果蝇作用作为我们的模型来研究HSPG在该途径中的作用。我们提出的研究的具体目的是：目标1。探索果蝇发育过程中HS修饰酶的分子功能。 AIM 2。探索HSPG在果蝇种系干细胞生态位中的作用。 AIM 3。在JAK/STAT途径中确定HSPG的角色。公共卫生相关性：硫酸乙酰肝素蛋白聚糖（HSPG）参与了多种生物学过程，例如生长因子信号传导，形态梯度形成和轴突指导。正常HSPG生物合成的破坏会导致许多人类遗传疾病以及癌症的形成。这项研究的长期目标是了解使用遗传学模型生物果蝇果蝇（Drosophila Melanogaster）在发育过程中HSPG功能和生物合成的分子基础。