Researcher: Yagna Jarajapu
Project Title: Angiotensin-(1-7), A Target For Boosting Stem/Progenitor Cell Mobilization In Diabetes
Diabetic vascular disease is the leading cause of mortality and morbidity worldwide. Impaired endothelial function and regeneration are the major causative factors for vascular disease. Bone marrow-derived stem/progenitor cells (BMPCs) play a potential role in vascular repair and offer a promising approach for the treatment of diabetic vascular disease. However, the success of the autologous cell therapies is mainly dependent on the efficiency of mobilization and collection of sufficient number of BMPCs, which is considerably lower in individuals with long-term diabetes. Furthermore, diabetic BMPCs are dysfunctional with reduced ability to induce regeneration therefore the approach of autologous cell therapies is currently not feasible in diabetic patients. Development of novel approaches is needed to boost mobilization and enhance the reparative potential of BMPCs in diabetes.
This investigator hypothesizes that the metabolite of angiotensin-converting enzyme (ACE)-2, Angiotensin (Ang)-(1-7), offers a novel target for boosting mobilization and function of BMPCs in diabetes basing on the following preliminary findings: 1) Ang-(1-7) increased the reparative potential of dysfunctional BMPCs from diabetic individuals. 2) Ang-(1-7) increased the circulating BMPCs in diabetic mice and stimulates their mobilization in response to vascular injury. 3) Ang-(1-7) decreased the oxidative stress and increased nitric oxide bioavailability in diabetic BMPCs. 4) Ang-(1-7) receptor, Mas is highly expressed in BM cells. The following specific aims are proposed to test the hypothesis. Specific Aim 1: Ang-(1-7) treatment enhances the mobilization of BMPCs by clinically used BM-mobilizers in diabetes. Specific Aim 2: Ang-(1-7) differentially modulates stromal and stem/progenitor cells to enhance the mobilization of BMPCs. The proposed aims will be pursued by a multidisciplinary approach using state-of-art-techniques in murine models of type 1 and type 2 diabetes.