This proposal describes a rigorous training program leading to the career development of Dr. Sarah Huen asan independent physician-scientist. The principal investigator is a board-certified nephrologist who recentlycompleted a Ph.D. program in Investigative Medicine at Yale University studying mechanisms of repair andfibrosis in ischemic kidney injury. Her career goal is to become an independent investigator studying sepsis-related acute kidney injury. She proposes to expand her training in immunobiology through an intensivetraining research experience under the mentorship of Dr. Ruslan Medzhitov, a pioneer in innate immunity andinflammation. In addition to didactic coursework and development of technical research skills in immunobiologyand sepsis, an advisory committee comprised of scientists and physician-scientists with a broad range ofexpertise related to the project will provide both scientific and career development guidance. The researchobjective of this proposal is to determine the role of the expression of Fibroblast growth factor-21 (FGF21) bythe kidney in the setting of sepsis. Preliminary data for this proposal reveal that in the mouse model oflipopolysaccharide (LPS) sepsis there is robust induction of FGF21 expression in the renal tubular epithelium.Mice deficient of FGF21 have more kidney dysfunction and are more susceptible to mortality in LPS sepsis.The induction of Fgf21 in the kidney is unique to sepsis as its expression is not induced in sterile hemodynamicinjuries. The expression of renal Fgf21 in LPS sepsis can be inhibited by the reactive oxygen species (ROS)scavenger n-acetylcysteine. Our hypothesis is that FGF21 is a ROS-inducible kidney tissue protective pathwaythat is activated in response to sepsis. This hypothesis will be tested by pursuing these aims: 1) Determine therole of renal FGF21 in promoting survival in sepsis, and 2) Identify the stress response pathway and the sourceof ROS that regulate Fgf21 gene expression. The Yale University Departments of Nephrology andImmunobiology together have extensive scientific resources that will enable the successful achievement ofthese proposed aims. This proposal will define a novel renal defense mechanism activated in response tosystemic infection while preparing the applicant to develop a successful independent research career as aphysician-scientist.
Patients who develop acute kidney injury in the setting of sepsis have a poor prognosis. Identifying protectivedefense mechanisms activated within the kidney during sepsis will contribute to the development oftherapeutics that can improve survival and limit kidney injury in sepsis.
| Wang, Andrew; Huen, Sarah C; Luan, Harding H et al. (2018) Glucose metabolism mediates disease tolerance in cerebral malaria. Proc Natl Acad Sci U S A 115:11042-11047 |
