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: 10839283
• 负责人: Alicia Marie Bedolla
• 金额: $ 4.06万
• 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/10839283
• 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; Central Nervous System Diseases; Cerebral Ischemia; Communication; Computer Models; Data; Development; Disease; Edema; Excision; Foundations; Functional disorder; Genes; Glial Fibrillary Acidic Protein; Goals; Hippocampus; Histologic; Homeostasis; Immune; Immunohistochemistry; Infarction; Infiltration; Inflammatory; Inflammatory Response; Injury; Ischemic Stroke; Knock-out; Knockout Mice; Knowledge; Learning; Ligands; Location; Locomotion; Magnetic Resonance Imaging; Maintenance; Mediating; Memory; Methods; Microglia; Modeling; Morphology; Motor; Mus; Nerve Degeneration; Neuroglia; Neurons; Neurotransmitters; Pathologic; Pathology; Pathway interactions; Peripheral; 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; Sorting; Stroke; Surveys; Synapses; Synaptic plasticity; TGF Beta Signaling Pathway; TGF-beta type I receptor; TGFBR2 gene; Tamoxifen; Testing; Time; Transforming Growth Factor beta; behavioral phenotyping; brain cell; cell type; central nervous system injury; chronic neurologic disease; cognitive function; disability; dosage; functional improvement; functional outcomes; inhibitor; insight; interest; mouse model; neuroinflammation; neuron loss; neuronal metabolism; neuronal survival; neurotransmission; novel; novel therapeutic intervention; object recognition; pathogen; pharmacologic; post stroke; receptor; response; stroke outcome; synaptic pruning; 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.

中风是全世界导致死亡和残疾的主要原因之一，给人们带来沉重的负担 在我们社会中的经济。近年来，人们认识到缺血性中风会引起强烈的神经炎性反应。 以小胶质细胞和星形胶质细胞大量激活和过度神经炎性反应为特征的反应 反应可能会影响卒中的长期结果。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 由中枢神经系统损伤或慢性神经疾病引起。我们的研究兴趣之一是描述如何 小胶质细胞影响星形胶质细胞的功能，最终决定神经元在这两种情况下的存活 生理和病理条件。转化生长因子-β最近被认为是导致 生理条件下成人脑内小胶质细胞稳态的维持。然而，它的作用是 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的反应 还没有被调查。转化生长因子-β药理调节剂(抑制剂和激活剂)表现出混合 在中风动物模型中，根据给药剂量和时间的不同，结果也相互矛盾。这些 研究结果强调了精确的时间和细胞类型特异性调节这一途径的重要性。至 精确研究转化生长因子-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 已经发展出一种小胶质细胞特异性的、可在时间上诱导的条件受体KO小鼠。我们的预赛 数据表明，转化生长因子-β信号在维持静息状态的中枢神经系统小胶质细胞特征谱中起重要作用 在生理条件下和消融转化生长因子-β信号在小胶质细胞不仅启动小胶质细胞的前 炎症状态，但也激活静止的星形胶质细胞。利用新的可诱导条件性KO小鼠品系， 我们将检验我们的中心假设：1)Alk5依赖的转化生长因子-β信号在血管内环境的动态平衡中起重要作用。 病理生理条件下小胶质细胞的功能及其与星形胶质细胞的串扰和2)调制 这一通路的缺失将导致中枢神经系统功能结果的改变。如果成功，将获得的知识 这一提议不仅限于中风研究，而且还可以对Alk5的作用产生更广泛的影响 其他中枢神经系统疾病中神经炎症调节和小胶质细胞-星形胶质细胞串扰的信号转导。