I am a practicing nephrologist and Co-Director of the Chronic Kidney Disease (CKD) clinic at Mayo Clinic, and member of the American Society of Nephrology Dialysis Advisory Group. My research to date has examined patient-important outcomes in dialysis, hypertension, and kidney transplant populations. 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). In my quest to improve the lives of patients with CKD, 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 a Master's degree in Clinical and Translational Science with a focus on regenerative medicine. My long-term goal is to become a leader in Regenerative Nephrology and an independent, productive clinician-investigator. My career development plan during the K23 period entails laboratory rotations, on-site and off-site clerkships in centers for regenerative medicine, individualized coursework, publications, collaborative network building, exposure through abstract presentations at national conferences, and experience with clinical trial protocol design and implementation. These endeavors 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. DN is the most prevalent cause of CKD and resistant to most interventions aimed at preventing progression. However, recent advances in regenerative medicine of adipose tissue-derived mesenchymal stromal/stem cell (MSC) transplantation offer hope. MSCs are non-embryonic stem cells with anti-fibrotic, anti-inflammatory, and pro-angiogenic paracrine activity that improve regeneration in DN models. However, patient-specific factors such as aging, obesity, uremia, and diabetes may decrease cellular function by inducing cellular senescence. 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. Our exciting new data reveal that cellular senescence, a central mechanism limiting MSC functional capacity, may be treatable through senolytic drugs that selectively eliminate senescent cells. In accordance, we showed that eradicating senescent cells improves stem cell function in animal models. Therefore, we plan to examine senolytic therapy as a potential in vivo preconditioning method to improve stem cell function. Our central hypothesis underlying the proposed studies is that adipose tissue-derived MSC obtained from patients with DN show increased senescence and decreased functionality, which can be ameliorated, both in vitro and in vivo, using drugs that clear senescent cells. This hypothesis will be pursued in 3 specific aims. First, we will compare cellular senescence and functionality in adipose tissue-derived MSC from patients with DN [estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73m2] to MSC from age- and gender-matched controls. Second, to determine the reversibility of DN-MSC dysfunction, we will incubate cells with senolytic agents in vitro and assess DN-MSC senescent cell clearance and function thereafter. Third, to examine the effect of senolytic agents on DN-MSC function in vivo, we will conduct a pilot study wherein DN patients (eGFR 15-45 mL/min/1.73m2) will receive senolytic drugs, and MSC senescence and function will be measured at baseline and 14 days after treatment with comparison to untreated controls. For each of these studies, DN patients will undergo 1-2 abdominal fat biopsies for MSC harvesting. Additional examinations will include blood and urine collection for diabetes, kidney function, and CKD-related measurements. Significance: Developing a safe and effective therapy to delay DN progression could reduce morbidity associated with dialysis, offer a better treatment option to a population often deferred for kidney transplantation, and produce extensive cost savings. These novel studies will advance the knowledge of the effects of cellular senescence on MSC, and help develop pre-screening protocols to optimize enrollment in trials using autologous MSC transplantation for DN. Furthermore, 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 the progression of DN. As a nephrologist, I am passionate about improving the lives of patients with CKD through innovative research. I believe my determination, clinical and research background, optimal and supportive institutional environment, and outstanding multidisciplinary mentoring and advisory team in combination with the protected time and funding from the K23 will propel me toward my goals of becoming an independent clinician-investigator and bringing stem cell therapy to patients with DN.

Public Health Relevance

Diabetic kidney disease is the most common cause of kidney failure in the United States and has no adequate cure. Stem cell transplantation is an exciting new treatment, with a potential to slow progression of kidney failure by injecting healthy stem cells to repair the kidney. However, if diabetes impairs their function, stem cells might be less effective. In this proposal, we will examine the feasibility of restoring the health of stem cells o that patients with diabetes might be able to benefit from participating in future stem cell transplant clinical trials for kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK109134-01
Application #
9086496
Study Section
Special Emphasis Panel (ZDK1-GRB-G (J2)M)
Program Officer
Rankin, Tracy L
Project Start
2016-07-01
Project End
2021-04-30
Budget Start
2016-07-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
$160,777
Indirect Cost
$11,734
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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