Functions of Discoidin Domain Receptor 1 in Diabetic Vascular Calcification and Regulation of Obesity and Type 2 Diabetes in High-fat Fed Mice

The extracellular milieu is a critical component of tissue structure and organization. The collagen-binding receptor tyrosine kinase Discoidin Domain Receptor 1 (DDR1) is an important sensor of the extracellular milieu that has been implicated in the pathogenesis of fibrosis, certain cancers, and atherosclerosis and vascular calcification. Due to its recent discovery, much remains to be learned about DDR1’s role in health and disease. In the present thesis, I describe a mechanism by which DDR1 promotes diabetic vascular calcification. In vivo, DDR1 deletion ameliorated diabetic vascular calcification and suppressed osteogenic transcription factor RUNX2. In vitro, DDR1 potentiated RUNX2 by the PI3K/Akt signaling axis. Downstream of Akt, GSK3β is an inhibitor of microtubule assembly and RUNX2. Microtubule organization was perturbed in DDR1 deficient cells and microtubule stabilization rescued nuclear RUNX2 translocation in DDR1-deficient cells. These findings demonstrate a novel pathway by which DDR1 promotes diabetic vascular calcification and implicate DDR1 in the regulation of microtubule assembly. Additionally, I discovered a novel function for DDR1 in the development of obesity-associated hyperglycemia and metabolic dysfunction. High fat feeding induced DDR1 expression in adipose tissue. Conversely, DDR1 deficient mice were leaner and were protected against metabolic dysfunction and had increased energy expenditure and UCP-1 expression in subcutaneous adipose tissue. In vitro, DDR1 inhibition blunted adipogenic differentiation of C3H10T1/2 cells and increased UCP-1 expression, whereas DDR1 overexpression suppressed UCP-1. These findings suggest that DDR1 deletion promotes beige fat formation whereas DDR1 suppresses it. Adipose tissue fibrosis is a known suppressor of beige fat formation and DDR1 has known functions in mediating fibrosis. Consistent with this, DDR1 deficient mice had decreased adipose tissue fibrosis, implicating DDR1 in the regulation of adipose tissue remodeling and whole-body energy metabolism, possibly by suppressing beige fat formation while concurrently promoting adipose tissue fibrosis. In conclusion, the research presented in this thesis demonstrates a signaling mechanism by which DDR1 promotes vascular calcification and uncovers a novel function of DDR1 in the regulation of adipogenesis, beige fat formation, and adipose tissue fibrosis. Taken together, these observations suggest that DDR1 is an important matrix sensor and determinant of cellular differentiation.Ph.D.2021-11-13 00:00:0