Regulation of Gliosis by Purinergic Receptor Signaling

嘌呤能受体信号传导对神经胶质增生的调节

• 批准号: 7082078
• 负责人: W Dalton Dietrich
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082078
• 关键词: G protein coupled receptor kinase; astrocytes; autoradiography; biological signal transduction; brain injury; cell growth regulation; cyclin dependent kinase; cyclins; enzyme linked immunosorbent assay; gliosis; immunocytochemistry; immunoprecipitation; in situ hybridization; laboratory mouse; laboratory rat; microarray technology; mitogen activated protein kinase; polymerase chain reaction; proliferating cell nuclear antigen; purinergic receptor; receptor expression; tissue /cell culture; western blottings

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.

描述（由申请人提供）：神经胶质增生是对脑损伤的反应，与许多常见的神经系统疾病相关，如创伤、中风、癫痫发作以及退行性和脱髓鞘性疾病。以星形胶质细胞对损伤的肥大和增生反应为特征的神经胶质增生通常被认为是再生的障碍，但反应性星形胶质细胞也具有神经营养特性，可以支持神经元生长和轴突导向。神经胶质增生发生的分子机制尚未明确，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在损伤时释放，并通过称为P2 Y（G蛋白偶联）和P2 X（配体门控离子通道）受体的ATP受体激活ERK级联。ATP受体，单独或组合碱性成纤维细胞生长因子（FGF 2），可以刺激或抑制星形胶质细胞生长，这可能取决于激活的受体类型和相关信号通路的性质。本申请的目的是确定ATP受体/ERK信号传导如何调节星形胶质细胞中细胞周期进展或生长停滞的承诺。这项研究的中心假设是，不同类型的ATP受体通过激活ERK级联反应不同的持续时间和强度以及通过调节细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂的不同谱的表达来调节细胞周期进程或停滞。该假设将通过以下方式进行检验：（1）确定由P2 Y和P2 X受体调节的Raf和ERK信号传导的强度的差异，（2）确定P2 Y和P2 X受体如何差异性地调节由FGF 2诱导的细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂的时间表达，以及（3）确定神经胶质化结果，如增殖、星座、以及参与轴突再生的分子的表达，这些分子在培养的星形胶质细胞和大鼠脑中受到P2 Y和P2 X受体的差异调节。这项研究是重要的，因为它将提供一个分子机制的理解，可以刺激或抑制反应性星形胶质细胞的形成。这可能提供了一个机会，以提高反应性星形胶质细胞的有益的，轴突生长促进功能，同时削弱其有害的，生长抑制性能。因此，在了解神经胶质增生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方法。

项目成果

Purinergic signaling induces thrombospondin-1 expression in astrocytes.

• DOI: 10.1073/pnas.0603146103
• 发表时间: 2006-06
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Minh D. Tran;J. Neary

Opposing effects of P2X(7) and P2Y purine/pyrimidine-preferring receptors on proliferation of astrocytes induced by fibroblast growth factor-2: implications for CNS development, injury, and repair.

• DOI: 10.1002/jnr.21765
• 发表时间: 2008-11-01
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Neary, Joseph T.;Shi, You-Fang;Kang, Yuan;Tran, Minh D.
• 通讯作者: Tran, Minh D.

P2 receptor signalling, proliferation of astrocytes, and expression of molecules involved in cell-cell interactions.

• DOI: 10.1002/9780470032244.ch11
• 发表时间: 2006
• 期刊: Novartis Foundation symposium
• 作者: J. Neary;Yuan Kang;You-fang Shi;Minh D. Tran;I. Wanner

Purinergic receptor signaling regulates N-cadherin expression in primary astrocyte cultures.

嘌呤能受体信号传导调节原代星形胶质细胞培养物中 N-钙粘蛋白的表达。

• DOI: 10.1111/j.1471-4159.2008.05214.x
• 发表时间: 2008
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Tran,MinhD;Wanner,InaB;Neary,JosephT
• 通讯作者: Neary,JosephT