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The novel matrix structures fractones promote FGF-2 in the neural stem cell niche

新型基质结构 fractone 促进神经干细胞生态位中的 FGF-2

基本信息

批准号：
7501942
负责人：
FREDERIC MERCIER
金额：
$ 16.79万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7501942
关键词：
Adult Affect Affinity Attention Basal lamina Basement membrane Binding Blood Vessels Brain Bromodeoxyuridine Cell Proliferation Cell Surface Receptors Cells Confocal Microscopy Connective Tissue Count Coupling Cues Data Degenerative Disorder Demyelinations Epidermal Growth Factor Extracellular Matrix Extracellular Structure Fibroblast Growth Factor Fibroblast Growth Factor 2 Goals Growth Factor Growth Factor Interaction Heparan Sulfate Proteoglycan Heparin Heparin Binding Heparin Binding Growth Factor Heparitin Sulfate Immunofluorescence Immunologic In Vitro Individual Injection of therapeutic agent Inorganic Sulfates Knockout Mice Mediating Meninges Mitotic Mus Nervous System Trauma Neuroglia Neurons Numbers Organ Pattern Peripheral Play Procedures Process Production Proliferating Publishing Role Signaling Molecule Stem cells Stratum Granulosum Structure System Tissues Tracer Transgenic Animals Transgenic Organisms Transplantation Trauma Unspecified or Sulfate Ion Sulfates Wild Type Mouse base dentate gyrus design extracellular immunocytochemistry in vivo lateral ventricle nerve stem cell neurogenesis neuroregulation novel perlecan prevent receptor relating to nervous system research study response spatial relationship stem sulfation

项目摘要

DESCRIPTION (provided by applicant): Neural stem and progenitor cells (NSPC) offer enormous potential for treating degenerative diseases or traumas of the nervous system. In adult mammalian species, NSC primarily reside in the lateral ventricle walls, where they proliferate and differentiate to produce new neurons and glial cells. It is now evident that microenvironmental cues regulate NSPC proliferation in the "niche" where the cells reside. However, the intrinsic systems that govern the neurogenic niche are poorly understood. Our overall goal is to understand how NSPC, endogenous or transplanted, function within an individual, to eventually replace lost cells. This fundamental understanding is crucial for designing new therapies for neural cells dying due to trauma, degeneration and demyelination. Based on our published data, we hypothesize that the new extracellular structures "fractones" we characterized in direct contact with NSPC in the neurogenic niche of the adult mammalian brain, mediate and regulate the production of new neurons and glial cells throughout adulthood. Our preliminary results indicate that the mechanisms implicated pertain to growth factor/extracellular matrix interactions at the NSPC/fractone interface. The objective of this proposal is to determine whether and how fractones intervene in the process of NSPC proliferation induced by the neurogenic growth factor FGF-2. We found that fractones bind and concentrate FGF-2 in vivo, by a mechanism that is heparan sulfate proteoglycan (HSPG) dependent. Our specific aims are to determine: 1) whether FGF-2 binding to fractones is responsible for FGF-2 induced neurogenesis in the niche; 2) whether NSPC proliferate in contact with fractones that have bound FGF-2; 3) the role of the fractone component perlecan (a major HSPG) on FGF-2-induced NSPC proliferation in the niche. For specific aim 1, we will use biotinylated FGF-2 as a tracer and inducer of NSPC proliferation, and heparatinase, both injected in vivo in the brain of adult mice to determine whether cutting the binding of biotinylated FGF-2 from fractone-borne HSPG annihilates neurogenesis induced by FGF-2. Immunofluorescence will be used to visualize post-mitotic cells that have incorporated bromodeoxyuridine and biotinylated FGF-2. For specific aim 2, we will use biotinylated FGF-2 to identify the spatial relationships between fractones that have bound biotinylated FGF-2 and the emerging cells that have proliferated in response to biotinylated FGF-2. For specific aim 3, we will use transgenic animals (perlecan-null mice) to determine how the lack of perlecan is detrimental to NSPC proliferation induced by biotinylated FGF-2 in the niche. These experiments will allow us to determine whether fractones promote NSPC proliferation induced by FGF-2 in the neural stem cell niche. If demonstrated, fractones will be considered as crucial components that regulate the neural stem cell niche throughout adulthood.

描述（由申请人提供）：神经干细胞和祖细胞（NSPC）在治疗退行性疾病或神经系统创伤方面具有巨大的潜力。在成年哺乳动物物种中，NSC主要存在于侧脑室壁，在那里它们增殖和分化产生新的神经元和神经胶质细胞。现在很明显，微环境信号调节NSPC在细胞所在的“生态位”中的增殖。然而，控制神经源性生态位的内在系统却知之甚少。我们的总体目标是了解NSPC，内源性或移植的，如何在个体内发挥作用，最终取代失去的细胞。这一基本认识对于设计治疗因创伤、退化和脱髓鞘而死亡的神经细胞的新疗法至关重要。根据我们发表的数据，我们假设在成年哺乳动物大脑的神经源性生态位中，与NSPC直接接触的新细胞外结构“碎片”，介导和调节整个成年期新神经元和神经胶质细胞的产生。我们的初步结果表明，涉及的机制与生长因子/细胞外基质在NSPC/ fracone界面上的相互作用有关。本研究的目的是确定分形酮是否以及如何干预神经源性生长因子FGF-2诱导的NSPC增殖过程。我们发现，在体内，分形酮通过一种依赖硫酸肝素蛋白多糖（HSPG）的机制结合和浓缩FGF-2。我们的具体目标是确定：1)FGF-2与分形酮的结合是否导致了FGF-2在生态位诱导的神经发生；2) NSPC是否在与FGF-2结合的分形物接触时发生增殖；3) fractone组分perlecan（一种主要的HSPG）在fgf -2诱导的NSPC增殖中的作用。对于特定的目的1，我们将使用生物素化的FGF-2作为NSPC增殖的示踪剂和诱诱剂，并在成年小鼠的大脑中注射肝素化酶，以确定切断生物素化的FGF-2的结合是否会消灭由FGF-2诱导的神经发生。免疫荧光将用于观察合并了溴脱氧尿苷和生物素化的FGF-2的有丝分裂后细胞。对于特定的目标2，我们将使用生物素化的FGF-2来确定结合生物素化的FGF-2的小碎片与生物素化的FGF-2反应增殖的新兴细胞之间的空间关系。对于特定的目标3，我们将使用转基因动物（无蜡质小鼠）来确定缺乏蜡质如何对生态位中生物素化的FGF-2诱导的NSPC增殖有害。这些实验将使我们能够确定分形酮是否促进神经干细胞壁龛中FGF-2诱导的NSPC增殖。如果证明，分形酮将被认为是调节整个成年期神经干细胞生态位的关键成分。