Molecular Signaling within a Regenerative Neurovascular Niche after Stroke

描述（由申请人提供）：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。这个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（成神经细胞）迁移到梗死周围组织的血管生成血管。神经新生和血管新生都与中风后的功能恢复有关。神经母细胞与梗死周围皮层血管生成血管的紧密联系形成了一种用于组织修复的细胞微环境，这是中风所特有的：再生的神经血管生态位。对再生神经血管生态位中的信号分子的理解可能为刺激神经发生、血管生成和功能恢复提供新的治疗方法。本资助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。PI的实验室是最早发现这一利基的实验室之一。这项资助的研究来自PI实验室的一组新数据，其中全基因组转录分析已经确定了中风后神经母细胞和血管生成血管之间相互作用的独特信号分子：再生神经血管相互作用组。该基因集包括所有受体/配体或分泌分子，它们能够在梗死周围皮层的神经母细胞及其邻近的血管生成血管之间相互作用。本基金的研究包括a

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.