Molecular Mechanisms of Axonal Sprouting and Recovery from 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，中风后确实会发生有限的自发修复和恢复过程。在脑卒中患者中，这种恢复与梗死周围和连接的皮质区感觉和运动功能的重新定位有关。在非人类灵长类动物和啮齿类动物模型中，中风通过称为轴突发芽的过程，在这些相同的区域诱导形成新的连接。我们最近在小鼠中风模型中表明，中风后运动和运动前皮层回路中的轴突发芽与运动恢复有因果关系。这些研究确定轴突发芽是促进中风后增强恢复的重要细胞靶点。脑卒中后的轴突发芽过程涉及成人皮层的三个关键步骤

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability. However, a limited and spontaneous process of repair and recovery does occur after stroke. In stroke patients this recovery is associated with re-mapping of sensory and motor functions in peri-infarct and connected cortical areas. In non-human primate and rodent models, stroke induces new connections to form in these same areas, by a process termed axonal sprouting. We have recently shown that in a mouse model of stroke, axonal sprouting in motor and premotor cortical circuits after stroke is causally associated with motor recovery. These studies identify axonal sprouting as an important cellular target in promoting enhanced recovery after stroke. The process of axonal sprouting after stroke involves three key steps for an adult cortical neuron: stroke sends a signal to adjacent neurons (a trigger), which activates a gene expression program (transcription factor), and the neuron then initiates axonal growth through the brain (extracellular signaling or adhesion proteins). We have recently identified a "sprouting transcriptome" of successfully sprouting neurons in peri-infarct cortex after stroke. When this transcriptome is analyzed with stringent statistical testing, and the genes associated with routine cytoskeletal structure removed, a small set of molecules are linked to the process of sprouting in neurons after stroke. Three molecules are highly regulated in sprouting neurons in relationship to these three key cellular steps in post-stroke axonal sprouting. Growth Differentiation Factor 10 (GDF10) is a bone morphogenic protein that is secreted after stroke (potential trigger). Bcl11b is a transcription factor that is also induced in sprouting neurons and has a normal function of promoting cortical axon growth in the developing brain. Matrilin-2 is an extracellular matrix protein that promotes peripheral nerve regeneration and is paradoxically down-regulated in cortical sprouting neurons after stroke. GDF10, Bcl11b and matrilin-2 have not been studied extensively in the adult brain, and have not been studied at all after stroke. Preliminary data links these three molecules to axonal sprouting in vitro and in vivo. The studies in this grant wil use pharmacological and genetic manipulation techniques to determine if these three molecules induce axonal sprouting, and then determine the patterns of motor and sensory maps in the living mouse over time that are associated with gain and loss of function in these molecular systems. Finally, the effect on motor control and recovery after stroke with gain and loss of function in these systems will be determined. This approach uses a novel experimental platform of detailed and structural mapping of brain connections, in vivo mapping of the functional physiology of these connections, and behavioral studies of recovery, for a "molecules to maps to behavior" approach to confirm highly promising molecular targets for post-stroke neural repair.