MOLECULAR AND CELLULAR CONTROL OF INJURY-INDUCED ASTROGENESIS

描述(由申请人提供)：尽管最近生物医学科学取得了进展，但中风或其他形式的脑损伤患者的治疗选择仍然有限。大脑的内源性再生能力为疾病和损伤后的神经系统修复提供了巨大的治疗希望。虽然近年来许多研究工作都集中在神经元的产生和整合上，但脑损伤后也会产生新的星形胶质细胞，而它们在修复过程中的功能重要性才刚刚开始被了解。与已被充分研究的成人神经发生领域相比，人们对健康和疾病中成人大脑中控制新星形胶质细胞产生的细胞和分子机制知之甚少。结合小鼠遗传学、分子生物学和多光子活体成像，我们计划阐明在脑损伤后产生新的星形胶质细胞和神经胶质瘢痕所必需的步骤，并了解它们在中风后反应和组织内稳态中的功能作用。我们的初步结果表明，细胞外基质蛋白Thrombospondin 4(Thbs4)对于胶质瘢痕的形成、阻止持续出血以及损伤后运动行为功能的恢复至关重要。此外，Thbs4和NFIA转录因子形成了一个信号轴，促进了损伤诱导的星形细胞形成。我们计划通过确定以下内容来进一步探索这些意想不到的观察：1)损伤后皮质胶质瘢痕的形成是否受来自SVZ利基的新生星形胶质细胞迁移到皮质损伤的特异性控制，和/或由新生成的星形胶质细胞递送的Thbs4蛋白本身介导，以作用于损伤部位的实质性星形胶质细胞/前体细胞；2)NFIA调控的转录途径是什么，以调控损伤诱导的星形胶质细胞的形成，这是启动胶质瘢痕形成所需的关键步骤；以及3)Thbs4表达的星形胶质细胞亚群是否构成一个祖细胞群体，可由Thbs4和NFIA蛋白作用于损伤后产生新的星形胶质细胞。研究控制损伤诱导的星形胶质细胞发生的基本细胞和分子机制，以及这些新的星形胶质细胞在组织动态平衡中所起的作用，应该会加深我们对星形胶质细胞生物学在健康和疾病中的理解。

DESCRIPTION (provided by applicant): Despite recent advances in biomedical sciences, treatment options remain limited for patients suffering from stroke or other forms of brain injuries. Endogenous regenerative capacities in the brain hold great therapeutic promise for nervous system repair after disease and injury. While in recent years much research effort has focused on production and integration of neurons, new astrocytes are also made following brain injury, and their functional importance during repair is just beginning to be understood. In contrast to the well- investigated area of adult neurogenesis, relatively little is known about the cellular and molecular mechanisms controlling new astrocyte production in the adult brain in health and disease. Using a combination of mouse genetics, molecular biology, and multiphoton live-imaging, we plan to elucidate the steps necessary to produce new astrocytes and glial scars after brain injury, as well as to understand their functional roles in post-stroke responses and tissue homeostasis. Our preliminary results show that extracellular matrix protein Thrombospondin 4 (Thbs4) is critically important for glial scar formation to stop continued bleeding, as well as motor-behavioral functional recovery after injury. Furthermore, Thbs4 and NFIA transcription factor form a signaling axis to promote injury-induced astrogenesis. We plan to further explore these unexpected observations by determining the following: 1) whether cortical glial scar formation after injury is specifically controlled by newly born astrocytes from the SVZ niche migrating to cortical injury, and/or mediated by Thbs4 protein itself, delivered by newly generated astrocytes to act on parenchymal astrocytes/progenitors at the injury site; 2) what are the transcriptional pathways controlled by NFIA to regulate injury-induced astrogenesis, the key step required to initiate glial scar formation; and 3) whether Thbs4-expressing astrocyte subset constitutes a progenitor population, that can be acted-on by Thbs4 and NFIA proteins to produce new astrocytes after injury. Tackling the basic cellular and molecular mechanisms controlling injury-induced astrogenesis, and the roles that these new astrocytes play in tissue homeostasis, should further our understanding of astrocyte biology in health and disease.