The Role of Activin-like kinase 5 (ALK5) for maintaining microglia and astrocyte homeostasis and activation

激活素样激酶 5 (ALK5) 在维持小胶质细胞和星形胶质细胞稳态和激活中的作用

• 批准号: 10388033
• 负责人: Alicia Marie Bedolla
• 金额: $ 3.97万
• 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: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388033
• 关键词: Ablation; Activins; Acute; Address; Adhesives; Adult; Affect; Animal Model; Anti-Inflammatory Agents; Antibodies; Area; Astrocytes; Behavioral; Behavioral Assay; Binding; Brain; Cause of Death; Cells; Central Nervous System Diseases; Cerebral Ischemia; Communication; Computer Models; Conflict (Psychology); Data; Development; Disease; Edema; Excision; Foundations; Functional disorder; Genes; Glial Fibrillary Acidic Protein; Goals; Hippocampus (Brain); Histologic; Homeostasis; Immune; Immunohistochemistry; Infarction; Infiltration; Inflammatory; Inflammatory Response; Injury; Ischemic Stroke; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Ligands; Location; Locomotion; Magnetic Resonance Imaging; Maintenance; Mediating; Memory; Methods; Microglia; Modeling; Morphology; Motor; Mus; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Neurotransmitters; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmacology; Phase; Phenotype; Phosphotransferases; Physiological; Recovery; Recovery of Function; Regulation; Reporter Genes; Reporting; Research; Research Proposals; Resolution; Rest; Role; Rotarod Performance Test; Sensory; Series; Severities; Signal Transduction; Societies; Stroke; Surveys; Synapses; Synaptic plasticity; TGF Beta Signaling Pathway; TGF-beta type I receptor; Tamoxifen; Testing; Time; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; base; behavioral phenotyping; brain cell; cell type; central nervous system injury; chronic neurologic disease; cognitive function; disability; dosage; functional outcomes; improved; inhibitor; insight; interest; mouse model; neuroinflammation; neuron loss; neuronal metabolism; neuronal survival; neurotransmission; novel; novel therapeutic intervention; object recognition; pathogen; post stroke; receptor; response; stroke outcome; transcriptome; transcriptome sequencing

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 an 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 determine 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 the 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 a microglia specific and temporally inducible 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) ALK5 dependent TGF-β signaling is important in the homeostasis of microglia function and its crosstalk 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 ALK5 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过量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，有时确定神经元的存活 生理和病理状况。最近已提出TGF-β是 在成人大脑的生理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 已经开发了特定于小胶质细胞和暂时诱导的受体条件KO小鼠。我们的初步 数据表明TGF-β信号传导对于维持静息中心小胶质细胞特征很重要 在物理状态和小胶质细胞中TGF-β信号传导的消融不仅是小胶质细胞的 炎症状态，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）依赖ALK5的TGF-β信号在体内稳态中很重要 小胶质细胞功能及其与星形胶质细胞在病理生理条件下的串扰，2）调节 该途径将导致CNS功能结果改变。如果成功，将获得的知识 该提议不仅限于中风研究，还可以对ALK5的作用产生更大的影响 神经炎症调节中的信号传导和其他中枢神经系统疾病中的小胶质细胞串扰。