MOLECULAR AND CELLULAR CONTROL OF INJURY-INDUCED ASTROGENESIS

描述（由申请人提供）：尽管生物医学科学取得了最新进展，但中风或其他形式脑损伤患者的治疗选择仍然有限。大脑中的内源性再生能力对于疾病和损伤后的神经系统修复具有巨大的治疗前景。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，它们在修复过程中的功能重要性才刚刚开始被理解。与成人神经发生的充分研究领域相反，对健康和疾病中控制成人脑中新星形胶质细胞产生的细胞和分子机制知之甚少。使用小鼠遗传学，分子生物学和多光子实时成像的组合，我们计划阐明脑损伤后产生新的星形胶质细胞和神经胶质瘢痕所需的步骤，以及了解它们在中风后反应和组织稳态中的功能作用。我们的初步研究结果表明，细胞外基质蛋白凝血酶敏感蛋白4（Thbs 4）是至关重要的胶质瘢痕形成，以阻止继续出血，以及运动行为功能恢复损伤后。此外，Thbs 4和NFIA转录因子形成信号传导轴以促进损伤诱导的星形细胞发生。1）损伤后皮质胶质瘢痕的形成是否由从SVZ龛迁移到皮质损伤的新生星形胶质细胞特异性控制，和/或由Thbs 4蛋白本身介导，由新生星形胶质细胞递送以作用于损伤部位的实质星形胶质细胞/祖细胞; 2）NFIA通过哪些转录途径调控损伤诱导的星形胶质细胞发生，这是启动胶质瘢痕形成的关键步骤;和3）表达Thbs 4的星形胶质细胞亚群是否构成祖细胞群，Thbs 4和NFIA蛋白可以在损伤后产生新的星形胶质细胞。解决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稳态中发挥的作用，应该进一步加深我们对健康和疾病中星形胶质细胞生物学的理解。

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.