Local Proliferation of Glia and their Interaction with Blood Vessels

神经胶质细胞的局部增殖及其与血管的相互作用

• 批准号: 8090244
• 负责人: Woo-Ping Ge
• 金额: $ 7.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090244
• 关键词: Acute; Address; Animals; Apoptosis; Astrocytes; Astrocytoma; Blood; Blood Vessels; Brain; Brain Edema; Brain Neoplasms; CSPG4 gene; Cells; Cerebral cortex; Cerebrovascular Circulation; DNA; Data; Development; Disease; Electrophysiology (science); Endothelial Cells; Functional disorder; Gene Mutation; Glioma; Goals; Image; In Situ Nick-End Labeling; In Vitro; Inherited; Ischemic Stroke; Label; Life; Lilium; Mediating; Mentors; Methods; Mitotic; Molecular; Mothers; Mus; Nerve Degeneration; Neuroglia; Neurons; Notch Signaling Pathway; Nutrient; Oligodendroglia; Outcome; Pathway interactions; Pericytes; Phase; Play; Population; Process; Production; Proliferating; Radial; Regulation; Research; Resolution; Rodent; Role; Slice; Source; Staging; Stroke; Structure; Supervision; Synaptic Transmission; Testing; Time; Transgenic Mice; base; density; design; glial cell development; improved; in vivo; innovation; loss of function; nervous system disorder; new therapeutic target; notch protein; novel; novel therapeutic intervention; postnatal; progenitor; research study; subventricular zone; synaptogenesis

DESCRIPTION (provided by applicant): My long-term goal is to elucidate mechanisms for glial development. The focus of this application is to characterize local proliferation of astrocytes in the cerebral cortex and the mechanism underlying their interaction with blood vessels at the postnatal stage. During postnatal weeks 2 and 3, the density of blood vessels and the number of glial cells both increase by ~4 fold in the rodent brain. It is still unclear where the large number of astrocytes come from and how they interact with blood vessels. My preliminary data show that postnatal local proliferation of astrocytes is widely distributed in different layers of the cerebral cortex, and these astrocytes retain their endfeet (perivascular processes of astrocytes) with blood vessels while they enter mitotic stages. I thus hypothesize that local prolifaration of astrocytes is a main source of cortical astrocytes that contribute to endfoot formation in the postnatal brain. To address the hypothesis, I propose two specific aims: (1) Characterize local proliferation of astrocytes and their fate and function in the cerebral cortex; (2) Elucidate the mechanism underlying endfoot formation around blood vessels mediated by locally generated astrocytes. I have established two groups of transgenic mouse lines to sparsely label astrocytes via genetically encoded fluorescent markers with unprecedented resolution, along with methods I developed to label and record dividing cells. I am therefore uniquely poised to undertake this novel study. Research proposed in the K99 Mentored phase (year 1 and 2) is concentrated on the establishment of methods for retroviral labeling and imaging of glial proliferation in live animals, which will be carried out with the supervision of Dr. Lily Jan. The R00 Independent phase (years 3 to 5) will focus on characterizing the function of astrocytes generated via local proliferation, and the mechanism underlying their interaction with blood vessels. The proposed research is innovative because it will provide the first direct evidence of postnatal local proliferation of astrocytes in cerebral cortex and show how they integrate into glial network and form endfoot structures with blood vessels. PUBLIC HEALTH RELEVANCE: The outcomes of these experiments will greatly improve our understanding of a variety of neurological diseases such as ischemic stroke and brain tumors caused by dysfunction of glial-vascular interaction or uncontrolled glial proliferation. Elucidation of the mechanism of formation of glial-vascular interaction will further facilitate development of new therapeutic targets for the treatment of these neurological diseases.

描述（由申请人提供）： 我的长期目标是阐明神经胶质细胞发育的机制。本申请的重点是表征大脑皮层中星形胶质细胞的局部增殖及其在出生后阶段与血管相互作用的机制。在出生后第2周和第3周，啮齿动物脑中的血管密度和神经胶质细胞数量均增加约4倍。目前还不清楚大量的星形胶质细胞来自哪里，以及它们如何与血管相互作用。我的初步数据显示，出生后局部增殖的星形胶质细胞广泛分布在大脑皮层的不同层，这些星形胶质细胞在进入有丝分裂阶段时保留其具有血管的端足（星形胶质细胞的血管周过程）。因此，我推测，局部增殖的星形胶质细胞是一个主要来源的皮质星形胶质细胞，有助于终足形成在出生后的大脑。为了解决这一假设，我提出了两个具体的目标：（1）表征星形胶质细胞的局部增殖及其在大脑皮层中的命运和功能;（2）阐明由局部产生的星形胶质细胞介导的血管周围终足形成的机制。我已经建立了两组转基因小鼠品系，通过遗传编码的荧光标记以前所未有的分辨率稀疏地标记星形胶质细胞，沿着我开发的标记和记录分裂细胞的方法。因此，我准备进行这项新颖的研究。在K99指导阶段提出的研究（第1年和第2年）集中于建立活动物中胶质细胞增殖的逆转录病毒标记和成像方法，这将在Lily Jan博士的监督下进行。（3至5年）将侧重于表征通过局部增殖产生的星形胶质细胞的功能，以及它们与血管相互作用的机制。这项研究具有创新性，因为它将提供大脑皮层星形胶质细胞出生后局部增殖的第一个直接证据，并显示它们如何整合到神经胶质网络中并与血管形成端足结构。 公共卫生相关性： 这些实验的结果将大大提高我们对各种神经系统疾病的理解，如缺血性中风和脑肿瘤，这些疾病是由神经胶质-血管相互作用功能障碍或不受控制的神经胶质增殖引起的。阐明胶质-血管相互作用的形成机制将进一步促进用于治疗这些神经系统疾病的新治疗靶点的开发。