The role TGF-beta Signaling pathway in microglia and astrocytes homeostasis and cellular interactions

中风是世界范围内死亡和残疾的主要原因之一， 经济在我们的社会。近年来，人们认识到缺血性脑卒中可引起强烈的神经炎症反应， 反应的特点是大量的小胶质细胞和星形胶质细胞活化，这种过度的神经炎性反应， 反应可能会影响中风的长期结果。我们实验室的长期目标是了解 决定神经元存活和神经修复的CNS组分，以改善功能结局 中枢神经系统损伤或慢性神经系统疾病。我们的研究兴趣之一是 小胶质细胞影响星形胶质细胞的功能，并最终决定神经元在两种情况下的存活。 生理和病理条件。TGF-β最近被认为是肿瘤发生的关键因素。 在成人脑中生理条件下维持小胶质细胞稳态。然而，其作用 在病理发展的不同阶段调节损伤诱导的小胶质细胞和星形胶质细胞反应 尚未被调查。TGF-β药理学调节剂（抑制剂和激活剂）已显示出混合的 在中风动物模型中，根据给药的剂量和时间，结果相互矛盾。这些 这些发现强调了该途径的精确时间和细胞类型特异性调节的重要性。到 为了精确研究TGF-β信号通路在小胶质细胞维持和星形胶质细胞串扰中的作用，我们 已经开发了多细胞类型特异性和时间诱导的配体或受体条件性KO小鼠。我们 初步数据表明，TGF-β信号传导在维持静息CNS小胶质细胞特征中是重要的 在生理条件下的曲线和小胶质细胞中的TGF-β信号传导的消融， 炎症前状态，但也激活静止的星形胶质细胞。利用新型诱导型条件性KO小鼠 我们将测试我们的中心假设：1）TGF-β信号在小胶质细胞的稳态中是重要的 功能及其在病理生理条件下与星形胶质细胞的相互作用，以及2）这种相互作用的调节 通路将导致改变的CNS功能结果。如果成功的话，我们将从中获得 这项提案不仅限于中风研究，而且还可能对TGF-β1信号转导在中风中的作用产生更广泛的影响。 神经炎症调节和小胶质细胞-星形胶质细胞串扰在其他CNS疾病。

Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Recently it has been recognized that ischemic stroke elicits a strong neuroinflammatory response characterized by massive microglia and astrocytes activation and this excessive neuroinflammatory response could affect the long-term outcome of stroke. The long-term goal of our lab is to understand key components of the CNS that determine neuronal survival and neurorepair, to improve functional outcomes from CNS injury or chronic neurological diseases. One of our research interests is to characterize how microglia cells affect the function of astrocytes and eventually determines the survival of neurons under both physiological and pathological conditions. TGF-β has recently been suggested as a key factor in the maintenance of microglia homeostasis under physiological conditions in adult brain. However, its role regulating injury-induced microglia and astrocyte responses during different stages of pathology development has not been investigated. TGF-β pharmacological modulators (inhibitors and activators) have shown mixed and conflicting results in stroke animal models, depending on the dosage and time of administration. These findings emphasize the importance of precise temporal and cell type specific modulation of this pathway. To precisely investigate the role of TGF-β signaling pathway in microglia maintenance and astrocyte crosstalk, we have developed multiple cell-type specific and temporally inducible ligand or receptor conditional KO mice. Our preliminary data indicates that TGF-β signaling is important in maintaining the resting CNS microglia signature profile under physiological condition and ablation of TGF-β signaling in microglia not only prime microglia cells to pre-inflammatory states, but also activate quiescent astrocytes. Utilizing novel inducible conditional KO mice lines, we will test our central hypotheses that 1)TGF-β signaling is important in the homeostasis of microglia function and its cross-talk with astrocytes under pathophysiological conditions and 2) that modulation of this pathway will lead to altered CNS functional outcome. If successful, the knowledge that will be gained from this proposal is not limited to stroke research but can also have broader impact on the role of TGF-β1 signaling in neuroinflammation regulation and microglia-astrocyte crosstalk in other CNS diseases.