The primary goal of this research program is to provide the applicant, Dr. Lisa M. Curtis, with new and intensive training in cell signaling and renal physiology and pathophysiology to expand her research tools with the purpose of becoming an independent VA investigator. To achieve this goal, Dr. Curtis will train in the fertile environment of the Birmingham VAMC and the University of Alabama at Birmingham (UAB), under the sponsorship of Paul W. Sanders, MD, Chief, Renal Section of the Birmingham VAMC and a Professor of Medicine at UAB. Additional mentoring will be provided by Dr. Anupam Agarwal, a staff physician at the Birmingham VAMC and Professor of Medicine and Division Director of Nephrology at UAB, and Dr. Christopher A. Klug, a Professor of Microbiology, Biochemistry and Genetics at UAB. Drs. Sanders, Agarwal and Klug have extensive experience in mentorship and have previously jointly provided Dr. Curtis with mentorship during her postdoctoral training at UAB. They each have unique expertise to facilitate accomplishing the scientific and professional training of Dr. Curtis that is necessary to achieve her long-term goals. The proposed studies will be the basis for training the applicant in the process used to study signaling pathways, particularly as applied to the study of hepatocyte growth factor (HGF) and stromal cell-derived factor 1 (SDF-1) , two known modulators of the pathophysiology of cellular repair in acute kidney injury (AKI). Additionally, these studies will expand the applicant's expertise in classical cell and molecular biology with an emphasis on renal pathophysiology. The scientific goals of this proposal are to elucidate the identity of renal cells that are capable of reconstitution of renal tubules and the signaling necessary to induce this reparative response. The overall hypothesis of the proposal is that renal reparative cells reside in the Fsp1+ cell population of the renal papilla and are recruited to sites of injury in response to the specific factors, HGF and SDF- 1. The proposal is divided into two specific aims.
The first aim utilizes an in vivo model of ischemia- reperfusion injury (IRI), a clinically relevant animal model, designed to elucidate the identity and dose-response of reparative cells that are recruited from the renal papilla in response to signals from the injured tissue.
This aim utilizes the powerful technique of the Cre-lox system in transgenic animals to mark specific cell populations in the kidney, which can then be tracked by histochemical and immunohistochemical techniques.
The second aim uses IRI to ascertain the impact of the presence or absence of signaling by HGF and/or SDF-1 on the repair of the epithelium.
This aim uses interference in the signaling pathways of these two agents through the use of neutralizing antibodies or pharmacologic agents. Similar to the first aim, this aim utilizes the outcome of the migration and incorporation of the marked reparative cells;as well, other indicators of injury and repair in AKI will be monitored for alterations. The career development plan includes attendance at seminars, workshops and other educational training opportunities at UAB, such as an advanced course in cell signaling, as well as training in the responsible conduct of research. The applicant will interact with senior members of the Renal Section, VAMC and the UAB Division of Nephrology. The Mentoring Plan includes formal and informal meetings with her three mentors, individually and together, which provide opportunities to address her training as an independent investigator as well as providing her with feedback on her professional and scientific progress. This Career Development Award will greatly enhance the applicant's professional development towards becoming an independent VA investigator.
Examination of the interaction of reparative renal cells in the environment of injury will provide greater understanding of the cellular pathways that underlie renal repair. Use of in vivo approaches will identify the inherent potential of putative reparative cells and the induction mechanisms in acute kidney injury (AKI). These studies are of direct relevance to the clinical care of patients at Veterans Affairs Medical Centers that frequently encounter patients with AKI secondary to a variety of causes. Existing treatment for AKI is limited to dialysis which is largely supportive. AKI has also been increasingly recognized as a cause for progressive chronic kidney disease leading to end-stage renal disease. This proposal will provide novel insight into the biology of repair following acute injury and holds the promise of advancing innovative therapies in the management of AKI.