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: 10538929
• 负责人: Yu Luo
• 金额: $ 55.37万
• 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/10538929
• 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; Conflict (Psychology); 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; Pharmacology; Phenotype; Physiological; Pilot Projects; Play; Production; Regulation; Research; Research Proposals; Rest; Role; Signal Transduction; Societies; Source; Spatial Distribution; Stroke; Synaptic plasticity; TGF Beta Signaling Pathway; TGF-beta type I receptor; 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 outcomes; improved; in vivo; inhibitor; injury recovery; insight; interest; ischemic injury; neuroinflammation; neuronal metabolism; neuronal survival; novel; novel therapeutic intervention; postnatal; receptor; response; small molecule; stroke outcome; transcriptome; 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.

中风是全球死亡和残疾的主要原因之一，对 我们社会的经济。最近，人们认识到缺血性中风会引起强烈的神经炎症性 反应以大量的小胶质细胞和星形胶质细胞激活和这种过多的神经炎症性为特征 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 确定神经元存活和神经层的CNS组件，以改善功能结果 来自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表征 小胶质细胞会影响星形胶质细胞的功能，有时决定两者下的神经元的存活率 生理和病理状况。最近已提出TGF-β是 在成人大脑的身体状况下维持小胶质细胞稳态。但是，它的作用 在病理发展的不同阶段，调节损伤引起的小胶质细胞和星形胶质细胞反应 尚未进行调查。 TGF-β药物调节剂（抑制剂和激活剂）已显示混合 根据剂量和给药时间，相互矛盾的结果是中风动物模型的结果。这些 发现强调了该途径的精确临时和细胞类型特定调制的重要性。到 精确地研究了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 已经开发了多种细胞类型的特异性和暂时诱导的配体或接收器有条件的KO小鼠。我们的 初步数据表明，TGF-β信号传导对于维持静止的CNS小胶质细胞特征很重要 小胶质细胞中TGF-β信号传导在物理状态下的剖面，不仅是主要小胶质细胞 在炎症前，但也激活静止的星形胶质细胞。利用新型的诱导条件KO小鼠 线，我们将测试中心假设，即1）TGF-β信号在小胶质细胞的稳态中很重要 在病理生理条件下的功能及其与星形胶质细胞的串扰和2）调节 途径将导致CNS功能结果改变。如果成功，那么从中获得的知识 提案不仅限于中风研究，而且还会对TGF-β1信号的作用产生更大的影响 其他中枢神经系统疾病中的神经炎症调节和小胶质细胞串扰。