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

TGF-β信号通路在小胶质细胞和星形胶质细胞稳态和细胞相互作用中的作用

• 批准号: 10620319
• 负责人: Yu Luo
• 金额: $ 48.85万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620319
• 关键词: Ablation; Acute; Adult; Affect; Animal Behavior; Animal Model; Astrocytes; Autocrine Communication; Behavioral; Brain; Cause of Death; Cells; Central Nervous System Diseases; Cerebral Ischemia; Cessation of life; Chronic; Computing Methodologies; Data; Development; Evaluation; Goals; Histologic; Homeostasis; Immune system; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Ischemic Stroke; Knock-out; Knockout Mice; Knowledge; Ligands; Maintenance; Mediating; Microglia; Neuroglia; Neuronal Injury; Neurons; Paracrine Communication; Pathologic; Pathology; Pathway interactions; Phenotype; Physiological; Pilot Projects; Play; Production; Proliferating; Recovery; Regulation; Research; Research Proposals; Rest; Role; Signal Transduction; Societies; Source; Spatial Distribution; Stroke; Synaptic plasticity; TGF Beta Signaling Pathway; TGF-beta type I receptor; TGFBR2 gene; Testing; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; brain tissue; cell type; central nervous system injury; chronic neurologic disease; cytokine; disability; dosage; functional improvement; functional outcomes; in vivo; inhibitor; insight; interest; ischemic injury; neuroinflammation; neuronal metabolism; neuronal survival; novel; novel therapeutic intervention; pharmacologic; postnatal; receptor; response; small molecule; stroke outcome; transcriptomic profiling; transcriptomics

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.

中风是全世界死亡和残疾的主要原因之一，给人们带来沉重负担 最近，人们认识到缺血性中风会引起强烈的神经炎症。 以大量小胶质细胞和星形胶质细胞激活为特征的反应以及这种过度的神经炎症 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关键。 中枢神经系统的组成部分决定神经元存活和神经修复，以改善功能结果 我们的研究兴趣之一是描述中枢神经系统损伤或神经系统疾病的特征。 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这两种情况下的存活 TGF-β最近被认为是该疾病的关键因素。 然而，其在生理条件下维持成人大脑中小胶质细胞稳态的作用。 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 尚未对 TGF-β 药理学调节剂（抑制剂和激活剂）进行研究。 中风动物模型中的结果相互矛盾，具体取决于给药剂量和时间。 研究结果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。 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 已开发出多种细胞类型特异性且可暂时诱导的配体或受体条件 KO 小鼠。 初步数据表明 TGF-β 信号传导对于维持静息中枢神经系统小胶质细胞特征非常重要 生理条件下的概况以及小胶质细胞中 TGF-β 信号传导的消融，而不仅仅是初级小胶质细胞 到炎症前状态，而且还利用新型可诱导条件 KO 小鼠激活静止的星形胶质细胞。 线，我们将测试我们的中心假设：1）TGF-β信号传导对于小胶质细胞的稳态很重要 功能及其在病理生理条件下与星形胶质细胞的串扰，2）对此的调节 如果成功，将导致中枢神经系统功能结果改变。 该提案不仅限于中风研究，还可以对 TGF-β1 信号传导在中风中的作用产生更广泛的影响。 其他中枢神经系统疾病中的神经炎症调节和小胶质细胞-星形胶质细胞串扰。