Mitochondrial Protection to Derive Expanded Aged Renal Glomerular Progenitor Cells Candidate: This K01 career development award application describes research and training activities for Mariya T. Sweetwyne, Ph.D. a renal cell biologist in the department of Pathology at the University of Washington, Seattle. Her immediate career goal is to combine her established training in renal biology with newly acquired and on-going training in the biology of cellular aging. Long-term, she intends to build an independent research program focused on developing interventions to ameliorate the impact of cellular aging on both chronic and acute renal glomerular diseases. In this application, Dr. Sweetwyne proposes specific aims to determine the role of mitochondrial dysfunction on the pathologies of aging glomerular epithelial cells. Research: Aging in the kidney is marked by fibrotic changes to the glomerular filtration units, which lead to increased risk of developing chronic kidney disease with advancing age. Previous studies from Dr. Sweetwyne et al. demonstrated that treating old mice with a tetrapeptide, Elamipretide (SS-31/Bendavia), to preserve mitochondrial inner membrane structure significantly reduced glomerular damage from renal aging, suggesting that one key to renal plasticity in the aged lies in mitochondrial health. This proposal builds on those findings to ask:
(Aim 1) which aspect of mitochondrial function is improved in specific glomerular epithelial cells, (Aim 2) how mitochondrial improvement results in observed reduction of glomerular cell senescence, (Aim 3) and whether these known enhancements will affect the regenerative potential of aged and depleted renal progenitor cells in mouse and man. Career Development Plan: This proposal serves Dr. Sweetwyne?s short and long-term goals by building her bench expertise in the biology of aging in three critical areas: (1) assessment of mitochondrial energetics, (2) utilization of proteomics, and (3) isolation and culture of primary human urine-derived progenitor cells. Professional academic development activities include: formal graduate course work in the biology of aging, presentation of research at national scientific conferences and routinely scheduled meetings with career mentors. Environment: The environment for Dr. Sweetwyne?s training at the University of Washington (UW) is exceptional. Her multidisciplinary mentoring team is comprised of senior faculty who are experts in mitochondrial energetics, aging biology, or nephrology. Dr. Sweetwyne?s principal mentor, Dr. Rabinovitch, is recognized as a leader in the field of aging and has successfully mentored multiple trainees through K01 and K99/R00 awards. Co-mentor Dr. David Marcinek of UW Radiology is an expert in mitochondrial energetics and oxidative stress in aging or injured muscle. Co-mentor Dr. Behzad Najafian of UW Pathology is a board certified Clinical Renal Pathologist and is expert in culture of human renal glomerular epithelium isolated from biopsies and urine. All mentors have established professional collaborations with Dr. Sweetwyne and are thus invested in the success of the scientific and professional aims outlined herein.
The kidneys of aging adults have increased susceptibility to renal injury from insults such as opportunistic infections, diabetes, and high fat diets and even from therapeutic interventions such as chemotherapy or surgery. Autologous stem cell transplant is rapidly evolving as a potential therapeutic to restore resiliency to aging kidneys, particularly in response to acute injury resulting from therapeutic intervention. With this proposal we ask the fundamental question in mice and humans: can reduction of aging mitochondrial dysfunction in vitro restore the expansion, survival and progenitor potential of aged urine-derived progenitor cells?