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

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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.