The role of FGF signaling in suppressing astrogliosis

FGF 信号在抑制星形胶质细胞增生中的作用

• 批准号: 8243428
• 负责人: JEAN M HEBERT
• 金额: $ 20.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243428
• 关键词: Address; Adult; Affect; Alleles; Astrocytes; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; Brain Injuries; Cell Death; Cells; Cerebrum; Cicatrix; Data; Epilepsy; FGF2 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Financial compensation; Future; Genes; Genetic Recombination; Glial Fibrillary Acidic Protein; Gliosis; Goals; Hippocampus (Brain); Immune; Inflammation; Infusion procedures; Injury; Intermediate Filaments; Ischemia; Ligands; Molecular; Mus; Natural regeneration; Nature; Nerve Degeneration; Neurons; Nuclear; Pharmaceutical Preparations; Phenotype; Puncture wound; Recovery; Refractory; Reporting; Role; Seizures; Severities; Signal Pathway; Signal Transduction; Specificity; Stroke; Structural Protein; Tamoxifen; Testing; Therapeutic; Tissues; Trauma; Vimentin; astrogliosis; base; cell type; in vivo; injured; mutant; neocortical; nervous system disorder; nestin protein; neuronal survival; receptor; research study; response; tumor growth

DESCRIPTION (provided by applicant): Gliosis is a response to brain damage and is a prominent feature of many neurological disorders including epilepsy, neurodegeneration, tumor growth, stroke, and trauma. The response to damage involves cell types from within the CNS and can include infiltrating immune cells. The extent of the response varies and is modulated by a number of secreted factors (Sofroniew, 2009; Kang and Hibert, 2011). For some of these factors, however, their requirement and role in gliosis has not been clearly defined or demonstrated in vivo. This is particularly true for Fibroblast Growth Factors (FGFs). Previous immunohistochemical analyses suggested that nuclear FGF2 and at least one receptor are up-regulated in astrocytes in response to damage (Eddleston and Mucke, 1993; Ridet et al., 1997). However, the significance of these immunostains is unknown. Moreover the role of FGF signaling in mature astrocytes in vivo under normal conditions as well as after injury remains unaddressed. The goal of this proposal is to provide definitive evidence for the role of FGFs in astrogliosis under normal conditions and in response to damage. To address the function of FGF signaling in the adult cerebrum, we conditionally deleted floxed alleles of Fgfr1 and Fgfr2 in an Fgfr3 null background. We used a NestinCreER mouse line in which CreER, upon tamoxifen treatment, is unexpectedly active specifically in astrocytes throughout the hippocampal and cortical parenchyma (in addition to the expected neurogenic regions). Our preliminary data indicate that in FGF receptor triple mutants there is a tremendous increase in astrocytic GFAP, Vimentin, and Nestin expression, indicative of astrogliosis. This increase in intermediate filaments is not observed in tamoxifen-treated heterozygous littermate controls that carry NestinCreER or in mutants that lack only one or two receptors. The absence of the phenotype in single and double mutants suggests functional compensation between receptors and may explain why this phenotype has not previously been reported. The increase in gliotic markers in the triple mutant is not accompanied by detectable signs of tissue damage, cell death, or obvious changes in the neurogenic regions. Moreover, our preliminary data suggests that the astrocytes that are reactive in the mutants are the ones that have lost FGF signaling whereas neighboring non-reactive ones have maintained signaling. This leads us to the hypothesis that FGF receptors act cell autonomously in the absence of injury to suppress astrogliosis. PUBLIC HEALTH RELEVANCE: In the brain, astrocytes are a cell type that responds to damage. Despite the importance of the response to damage, the molecular mechanisms that control it remain poorly understood. The degree of the response depends on the type and severity of the damage. For example, in some cases astrocytes form scar tissue and it some cases they do not. Although scar formation is essential to minimizing the spread of damage, it is also refractory to regeneration. Therefore the degree of the response to damage is believed to be tightly regulated by secreted factors, intracellular signaling factors, and structural proteins (intermediate filaments). One family of factors that has been postulated to promote the astrocyte response, despite the lack of definitive evidence, are FGFs. In this proposal, however, we aim to provide the first definitive evidence to the contrary: that FGFs in fact inhibit the astrocyte response. This is significant because there are few if any other clear examples of factors that maintain the response in check in the unperturbed brain and after injury. Our preliminary data suggest that FGF signaling is required in adults to actively suppress the astrocyte response, even in the absence of injury. Hence this provides a potential means of modulating the extent or duration of the response for therapeutic purposes.

描述（由申请人提供）：神经胶质增生是对脑损伤的反应，是许多神经系统疾病的显著特征，包括癫痫、神经变性、肿瘤生长、中风和创伤。对损伤的反应涉及CNS内的细胞类型，并且可以包括浸润性免疫细胞。反应的程度各不相同，并受到许多分泌因子的调节（Sofroniew，2009; Kang和Hibert，2011）。然而，对于这些因素中的一些，它们在神经胶质增生中的需求和作用尚未明确定义或在体内证明。这对于成纤维细胞生长因子（FGF）尤其如此。先前的免疫组织化学分析表明，核FGF 2和至少一种受体在星形胶质细胞中响应于损伤而上调（Eddendt和Mucke，1993; Ridet等人，1997年）。然而，这些免疫染色的意义是未知的。此外，FGF信号传导在正常条件下以及损伤后体内成熟星形胶质细胞中的作用仍然没有得到解决。该提案的目的是提供明确的证据，在正常条件下，在星形胶质细胞增生的FGF的作用，并在损害的反应。为了解决FGF信号传导在成人大脑中的功能，我们在Fgfr 3无效背景中有条件地删除Fgfr 1和Fgfr 2的floxed等位基因。我们使用了NestinCreER小鼠系，其中CreER在他莫昔芬治疗后，在整个海马和皮质实质中的星形胶质细胞中（除了预期的神经原性区域之外）具有出乎意料的特异性活性。我们的初步数据表明，在FGF受体三重突变体中，星形胶质细胞GFAP、波形蛋白和巢蛋白表达显著增加，表明星形胶质细胞增生。在携带NestinCreER的他莫昔芬处理的杂合同窝对照或仅缺乏一种或两种受体的突变体中未观察到中间丝的增加。在单突变体和双突变体的表型的情况下，表明受体之间的功能补偿，并可能解释为什么这种表型以前没有被报道。三重突变体中胶质细胞标记物的增加并不伴随着可检测到的组织损伤、细胞死亡或神经源性区域的明显变化的迹象。此外，我们的初步数据表明，在突变体中具有反应性的星形胶质细胞是已经失去FGF信号传导的星形胶质细胞，而邻近的非反应性星形胶质细胞保持了信号传导。这导致我们假设FGF受体在没有损伤的情况下自主作用于细胞以抑制星形胶质细胞增生。 公共卫生相关性：在大脑中，星形胶质细胞是一种对损伤做出反应的细胞类型。尽管对损伤的反应很重要，但控制它的分子机制仍然知之甚少。反应的程度取决于损害的类型和严重程度。例如，在某些情况下，星形胶质细胞形成疤痕组织，而在某些情况下，它们不形成疤痕组织。虽然疤痕形成是必不可少的，以尽量减少损害的蔓延，它也是难再生的。因此，对损伤的反应程度被认为受到分泌因子、细胞内信号传导因子和结构蛋白（中间丝）的严格调节。尽管缺乏明确的证据，但已被假定促进星形胶质细胞反应的一个因子家族是FGF。然而，在这个提议中，我们的目标是提供相反的第一个明确证据：FGF实际上抑制星形胶质细胞的反应。这一点很重要，因为在未受干扰的大脑中和受伤后，几乎没有其他明确的例子来证明维持反应的因素。我们的初步数据表明，即使在没有损伤的情况下，成年人也需要FGF信号传导来积极抑制星形胶质细胞的反应。因此，这为治疗目的提供了调节反应的程度或持续时间的潜在手段。