Regulation of Gliosis by Purinergic Receptor Signaling

描述(申请人提供)：脑胶质细胞增多症是对脑损伤的反应，与许多常见的神经系统疾病有关，如创伤、中风、癫痫、退行性和脱髓鞘疾病。胶质增生症的特点是星形胶质细胞对损伤的肥大和增生性反应，通常被认为是再生的障碍，但反应性星形胶质细胞也具有支持神经元生长和轴突引导的神经营养特性。胶质细胞增生症发生的分子机制尚不清楚，但其中一种机制可能涉及细胞外信号调节蛋白激酶(ERK)和Raf，它们是在增殖和分化中重要的信号转导级联的关键成员。ATP在损伤时被释放，并通过被称为P2Y(G蛋白偶联)和P2X(配体门控离子通道)的ATP受体激活ERK级联反应。ATP受体单独或联合碱性成纤维细胞生长因子(FGF2)可以刺激或抑制星形胶质细胞的生长，这可能取决于激活的受体的类型和相关信号通路的性质。这项应用的目的是确定ATP受体/ERK信号如何调节星形胶质细胞对细胞周期进程或生长停滞的承诺。这项研究的中心假设是，不同类型的ATP受体通过激活不同持续时间和强度的ERK级联，以及通过调节不同类型的细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂的表达，来调节细胞周期的进展或停滞。检验这一假说的方法包括：(1)确定受P2Y和P2X受体调控的Raf和ERK信号强度的差异；(2)确定P2Y和P2X受体如何以不同的方式调控FGF2诱导的细胞周期蛋白和细胞周期蛋白依赖的激酶抑制物的瞬时表达；(3)确定由P2Y和P2X受体在培养的星形胶质细胞和大鼠脑组织中进行差异调控的胶质细胞结局，例如增殖、星形和轴突再生相关分子的表达。这项研究具有重要意义，因为它将提供对刺激或抑制反应性星形胶质细胞形成的分子机制的理解。这可能提供一个机会来增强反应性星形胶质细胞有益的、促进轴突生长的特性，同时减弱它们有害的、抑制生长的特性。因此，在理解胶质细胞增多症的机制方面取得的重要进展可能为恢复脑损伤引起的运动技能和认知功能缺陷提供新的途径。

DESCRIPTION (provided by applicant): Gliosis occurs in response to brain injury and is associated with many common neurological conditions such as trauma, stroke, seizure, and degenerative and demyelinative disorders. Gliosis, which is characterized by the hypertrophic and hyperplastic response of astrocytes to injury, is often regarded as an impediment to regeneration, but reactive astrocytes also possess neurotrophic properties that can support neuronal growth and axonal guidance. The molecular mechanisms that underlie the development of gliosis are not well defined, but one such mechanism may involve extracellular signal regulated protein kinase (ERK) and Raf, key members of a signal transduction cascade important in proliferation and differentiation. ATP is released upon injury and activates the ERK cascade via ATP receptors termed P2Y (G protein-coupled) and P2X (ligand-gated ion channel) receptors. ATP receptors, alone or in combination basic fibroblast growth factor (FGF2), can stimulate or inhibit astrocyte growth, depending perhaps on the type of receptor activated and the properties of the associated signaling pathway. The objective of this application is to determine how ATP receptor/ERK signaling regulates the commitment to cell cycle progression or growth arrest in astrocytes. The central hypothesis for the proposed research is that distinct types of ATP receptors regulate cell cycle progression or arrest by activating the ERK cascade for different durations and intensities and by regulating expression of different profiles of cyclins and cyclin-dependent kinase inhibitors. This hypothesis will be tested by (1) determining differences in the strength of Raf and ERK signaling regulated by P2Y and P2X receptors, (2) determining how P2Y and P2X receptors differentially regulate the temporal expression of cyclins and cyclin-dependent kinase inhibitors induced by FGF2, and (3) determining gliotic outcomes, such as proliferation, stellation, and the expression of molecules involved in axonal regeneration, that are differentially regulated by P2Y and P2X receptors on cultured astrocytes and in rat brains. This research is significant because it will provide an understanding of molecular mechanisms that can stimulate or inhibit the formation of reactive astrocytes. This may offer an opportunity to enhance the beneficial, axonal growth-promoting features of reactive astrocytes while attenuating their harmful, growth-inhibiting properties. Thus, important advances in the understanding of the mechanisms underlying gliosis may provide new approaches to restore deficits in motor skills and cognitive functions caused by brain injury.