Mesenchymal stem cell senescence in diabetic nephropathy (K23 COVID Admin Supplement)

项目总结/文摘

PROJECT SUMMARY/ABSTRACT I am a practicing nephrologist at Mayo Clinic and I will use the acquired skills from my clinical and epidemiology background to bring the proposed basic research investigations into truly translational research for patients with diabetic nephropathy (DN). I have assembled a multidisciplinary team of mentors who will provide guidance, infrastructure, and tools needed for performance of the proposed studies. My immediate career goal is to gain laboratory research skills, clinical trial experience, regenerative medicine fund-of- knowledge, and regenerative medicine coursework. My long-term goal is to become a leader in Regenerative Nephrology and an independent, productive clinician-investigator. My career development plan will provide me with the building blocks needed to transition into independence. I have the strongest support from my division, department, and institution. In the proposed studies, I will explore the feasibility of a novel therapeutic platform that I believe may change the course of disease and improve the lives of patients with DN, a devastating disease with few therapeutic options. Mesenchymal stromal/stem cell (MSC) transplantation offers hope. MSCs are non-embryonic stem cells with anti-fibrotic, anti-inflammatory, and pro-angiogenic paracrine activity that improve regeneration in DN models. Senescence is an irreversible cell cycle arrest, which generates a pro-inflammatory secretory phenotype that impairs neighboring cell function. Hence, increased senescent cell burden in DN may substantially compromise MSC function and become a barrier to successful autologous MSC transplantation. Our overall goal is to characterize and optimize the functional properties of MSC in DN to allow these patients to benefit from future enrollment in clinical trials using stem cell transplantation. A central mechanism limiting MSC functional capacity, may be treatable through senolytic drugs that selectively eliminate senescent cells. We will examine senolytic therapy as a potential in vivo preconditioning method to improve stem cell function. Our central hypothesis is that adipose-derived MSC obtained from DN patients show increased senescence and decreased functionality, which can be ameliorated, both in vitro and in vivo, using drugs that clear senescent cells. First, we will compare cellular senescence and functionality in MSC from DN patients to MSC from age- and gender-matched controls. Second, we will incubate cells with senolytic agents in vitro and assess DN-MSC senescent cell clearance and function thereafter. Third, we will conduct a pilot study wherein DN patients will receive senolytic drugs, and MSC senescence and function will be measured at baseline and 14 days after treatment. Additional examinations will include blood and urine collection for kidney function and injury measurements. The proposed studies explore an innovative approach for preconditioning MSC and their deleterious microenvironment, and aid in developing a completely novel therapeutic strategy to delay DN progression.