Molecular Signaling within a Regenerative Neurovascular Niche after Stroke

描述(申请人提供)：中风是导致成人残疾的主要原因。然而，中风后的修复和恢复过程是有限的。这一过程与中风附近组织中新神经元的形成(神经发生)和新血管的形成(血管生成)有关。神经发生和血管生成密切相关，因为新生的神经元(神经母细胞)迁移到梗塞周围组织中的血管生成。神经再生和血管生成都与中风后的功能恢复有关。神经母细胞与梗塞周围皮质血管新生血管的紧密联系形成了中风所特有的用于组织修复的细胞微环境：一个再生的神经血管利基。对再生神经血管内信号分子的了解可能会为刺激神经发生、血管生成和功能恢复的新疗法提供帮助。这项资助中的研究确定了再生神经血管壁龛中候选信号分子的组织修复和恢复机制。私家侦探的实验室是最早发现这一利基市场的实验室之一。这项拨款的研究源于PI实验室的一个新数据集，在该数据集中，全基因组转录图谱确定了中风后神经母细胞和血管新生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体。这个基因集由所有的受体/配体或分泌分子组成，这些分子位于梗死区周围皮质中神经母细胞与其邻近的血管新生血管之间相互作用的位置。这项资助中的研究涉及一项 利用在再生神经血管相互作用体中确定的四个最重要的基因，采用系统获得和功能丧失的方法，确定卒中后梗塞周围皮质血管新生内皮细胞到神经母细胞和神经母细胞到内皮细胞的候选信号分子。这些研究使用了新的方法来研究神经血管生态位内的功能获得和丧失，转基因小鼠系来专门测试中风后增强神经发生和血管生成的行为效应，以及一个测试这些候选信号系统的机制作用的平台，从体外到体内再到行为恢复研究。

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.