Molecular Signaling within a Regenerative Neurovascular Niche after Stroke

中风后再生神经血管生态位内的分子信号传导

• 批准号: 8577860
• 负责人: Stanley Thomas Carmichael
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577860
• 关键词: Adult; Applications Grants; Area; Behavioral; Behavioral Assay; Binding; Blood Vessels; Brain; Data Set; Endothelial Cells; Environment; Gene Expression Profiling; Genes; Genome; Glycoproteins; Grant; Human; In Vitro; Infarction; Injury; Interleukin 7 Receptor; Knockout Mice; Ligands; Link; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Measures; Molecular; Natural regeneration; Nonmetastatic; Positioning Attribute; Process; Recovery; Recovery of Function; Rodent Model; Role; Signal Transduction; Signaling Molecule; Stroke; System; Testing; Tissues; Transgenic Mice; adult neurogenesis; angiogenesis; base; disability; human TSLP protein; improved; in vivo; loss of function; melanoma; neural precursor cell; neuroblast; neurogenesis; neuromechanism; novel; novel strategies; post stroke; progenitor; public health relevance; receptor; regenerative; relating to nervous system; repaired; stem; subventricular zone; tissue regeneration; tissue repair

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability. However, a limited process of repair and recovery occurs after stroke. This process is associated with the formation of new neurons (neurogenesis) and the formation of new blood vessels (angiogenesis) in the tissue adjacent to the stroke. Neurogenesis and angiogenesis are intimately linked, in that newly born neurons (neuroblasts) migrate to angiogenic blood vessels in peri-infarct tissue. Both neurogenesis and angiogenesis are linked to functional recovery after stroke. The tight association of neuroblasts with angiogenic blood vessels in peri-infarct cortex forms a cellular microenvironment for tissue repair that is unique to stroke: a regenerative neurovascular niche. An understanding of the signaling molecules within the regenerative neurovascular niche may provide for novel therapies that stimulate neurogenesis, angiogenesis and functional recovery. The studies in this grant determine the mechanisms of tissue repair and recovery of candidate signaling molecules in the regenerative neurovascular niche. The PI's lab was among the first to identify this niche. The studies in this grant follow from a novel data set from the PI's lab, in which whole genome transcriptional profiling has identified the unique set of signaling molecules that interact between neuroblasts and angiogenic vessels after stroke: the regenerative neurovascular interactome. This gene set consists of all the receptor/ligand or secreted molecules that are in a position to interact between neuroblasts and their adjacent angiogenic blood vessels in peri-infarct cortex. The studies in this grant involve a systematic gain and loss of function approach to identify the candidate signaling molecules from angiogenic endothelial cell-to-neuroblast and from neuroblast-to-endothelial cell in peri-infarct cortex after stroke, using the four most important genes identified in the regenerating neurovascular interactome. These studies use novel approaches for gain and loss of function studies within the neurovascular niche, transgenic mouse lines to specifically assay the behavioral effect of enhancing neurogenesis and angiogenesis after stroke and a platform that tests the mechanistic roles of these candidate signaling systems from in vitro to in vivo to behavioral recovery studies.

描述（由申请人提供）：中风是成人残疾的主要原因。然而，中风后的修复和恢复过程有限。这个过程与中风附近组织中新神经元（神经发生）和新血管（血管生成）的形成有关。神经发生和血管生成密切相关，因为新生神经元（成神经细胞）迁移到梗死周围组织中的血管生成血管。神经发生和血管生成都与中风后的功能恢复有关。梗死周围皮层中神经母细胞与血管生成血管的紧密联系形成了中风特有的组织修复的细胞微环境：再生神经血管生态位。了解再生神经血管生态位内的信号分子可能提供刺激神经发生、血管生成和功能恢复的新疗法。这项研究确定了再生神经血管生态位中组织修复和候选信号分子恢复的机制。PI的实验室是最早发现这个利基市场的实验室之一。这项研究来自PI实验室的一个新数据集，其中全基因组转录谱已经确定了中风后成神经细胞和血管生成血管之间相互作用的独特信号分子集：再生神经血管相互作用组。该基因组由所有受体/配体或分泌分子组成，这些分子能够在成神经细胞和其邻近的梗死周围皮层中的血管生成血管之间相互作用。该补助金中的研究涉及 系统性功能获得和丧失的方法，以确定候选信号分子从血管生成内皮细胞到神经母细胞和从神经母细胞到内皮细胞在梗死周围皮层中风后，使用四个最重要的基因中确定的再生神经血管相互作用。这些研究使用新的方法进行神经血管生态位内的功能获得和丧失研究，转基因小鼠系特异性地测定中风后增强神经发生和血管生成的行为效应，以及测试这些候选信号系统从体外到体内到行为恢复研究的机制作用的平台。