This proposal describes a 5-year research training and career development plan designed to facilitate Dr. Pan?s transition from junior to independent investigator. She completed Internal Medicine residency and a T32 Nephrology Research Fellowship at Baylor. She joined BCM as an Assistant Professor in Nephrology in July 2013. The application is devised to make use of research resources and expertise of successful investigators at BCM. Dr. Pan has created a Career Advisory Committee consisting of senior investigators dedicated to mentoring young scientists to provide guidance with her research and career development. Dr. David Sheikh- Hamad, Professor of Medicine (Nephrology) at BCM, will serve as her primary mentor. He is funded by a VA Merit award and NIH R01 and is an expert in renal inflammation, ischemia/reperfusion (I/R) kidney injury, and the anti-oxidant actions of stanniocalcins. Her co-advisors are: 1) William E. Mitch, MD, an expert in muscle metabolism; 2) Qiang Tong, PhD, an innovator in sirtuin research; 3) Lee-Jun Wong, PhD, an expert in mitochondrial genetics and function; and 4) Vijay Yechoor, MD, a successful investigator in insulin resistance and diabetes. Dr. Pan?s career development plan includes frequent meetings with her mentors, didactics to increase scientific knowledge, and attending conferences to present her research. Acute kidney injury (AKI) is common and associated with increased morbidity/mortality, and progression to chronic kidney disease. However, the therapeutic options for AKI remain limited. ATP/nutrient depletion and oxidative stress play important roles in the pathogenesis. Our data suggest that stanniocalcin-1 (STC1) suppresses ROS and confers resistance to I/R kidney injury (a model for ischemic AKI) through AMPK activation, preferentially the AMPK?2 isoform. Moreover, STC1 induces the mitochondrial longevity gene SIRT3 via AMPK activation. SIRT3 has been shown to suppress ROS, and this grant will test the Central Hypothesis that: STC1/AMPK?2/SIRT3 is an inducible and adaptive energy sensing pathway that suppresses mitochondrial superoxide production and protects from I/R kidney injury. Using in vitro hypoxia/reoxygenation injury model, Aim I will examine whether selective siRNA knockdown of AMPK?2 diminishes STC1-induced cytoprotection and SIRT3 expression. Using double mutant STC1 Tg/AMPK?1 KO or STC1 Tg/AMPK?2 KO mice, Aim II will examine in vivo whether STC1-induced renoprotection is mediated through preferential activation of AMPK?2. Using SIRT3 Tg and SIRT3 KO mice, as well as in vitro overexpression or siRNA- mediated knockdown of SIRT3, Aim III will determine whether SIRT3 overexpression is protective from ischemic kidney injury.
Aim I V will examine the role of SIRT3 in the observed sexual dimorphism in ischemic AKI, and the effect of sex hormone modulation on SIRT3/AMPK expression. Our studies identify STC1/AMPK?2/SIRT3 as novel therapeutic targets for the treatment of ischemic AKI, and the proposed aims will characterize and further define the role of SIRT3 and AMPK?2 in kidney protection. The research environment at BCM is ideal for fostering the continued education and development of young physician investigators. Dr. Pan will benefit from outstanding mentoring and strong institutional support.
Kidney failure is associated with a high rate of complications and death, and the options for treatment are limited. Our results show that mice engineered to produce large amounts of stanniocalcin-1 protein are resistant to insults that normally cause kidney failure. Stanniocalcin-1 reduces oxidant stress in many cells and organs and appears to work through AMPK and the longevity protein SIRT3; of note, the levels of AMPK and SIRT3 vary with age and gender. This proposal will study the role of AMPK and SIRT3 in acute kidney injury, including gender differences in the susceptibility to injury and response to therapy. Our results could lead to new therapies for kidney failure.