Director:
Paul W. Sanders, M.D., Univ of Alabama at Birmingham
The principal objective of the UAB-UCSD O’Brien Center Pilot and Feasibility (PAF) Program is to provide seed funds for new, outstanding, and innovative research proposals related to AKI. These pilot funds will provide eligible investigators with one to two years of support along with the resources necessary to explore investigator-initiated projects related to AKI.
The UAB-UCSD O’Brien Center PAF Program will have a tri-partite focus with a mission 1)to attract junior faculty to AKI-related research; 2) enable established investigators to explore the feasibility of new, innovative concepts in AKI-related research; and 3) entice investigators with research expertise in the Core Center’s thematic areas to apply their expertise to AKI-related questions.
The ultimate goal of the UAB-UCSD O’Brien Center PAF program is to provide sufficient resources and training for pilot investigators to pursue additional funding of AKI-related research through extramural mechanisms.
Description of the Pilot and Feasibility Program
Eligibility criteria
- New independent investigators (Instructor or Assistant Professor) who do not have current or past NIH research support (R01 or P01 level) and who have an interest in AKI-related research. This funding opportunity is open to investigators at UAB, UCSD, as well as outside institutions involved in research. Recipients of K awards (K01, K08 or K23) will be eligible.
- Established investigators who have not worked in the field of AKI but want to explore a novel concept related to AKI or apply their expertise to a problem in this area.
With a pilot study award, faculty will automatically become members of the O’Brien Center. Pilot award recipients will not be charged for the use of Core services (within reason) pertinent to their PAF project. Once the funding period is completed, the faculty member’s continued membership in the Center will be at the discretion of the Center Director, Co-Directors, and Internal Advisory Committee and will depend upon continued research and extramural funding pertinent to AKI.
For non-center faculty, preference will be given to either young investigators or those more established investigators seeking to explore the feasibility of a new concept relevant to AKI-related research or developing a collaborative project with a Center member from the Internal or the Extended Research Base.
Funded investigators will be expected to present their findings at the annual Comprehensive Research Symposium that will alternate between UAB and UCSD. In addition, Pilot Project recipients will be encouraged to present their work at the Annual meeting of the American Society of Nephrology where a formal half-day meeting of Center participants will be organized either immediately prior to or after the conference.
Solicitation of the Pilot and Feasibility Proposals
We will circulate a Request for Proposals (RFP) four months prior to the award date (usually July 1) that will be distributed to all UAB-UCSD faculty by posting in local newsletters, notice boards, and e-mail and distributed to all members of the Extended Research Base by e-mail. A two-phased application process will be used.
First level review
Interested investigators are asked to submit a two-page (1” margins, single-space, Arial 11-size font) description of the project that includes separate sections on overall objectives, a testable hypothesis with specific aims, significance of the proposed research to acute kidney injury, and experimental plan summary. This will be due within one month of the RFP announcement. The PAF program committee will review applications. Emphasis will be placed on scientific merit, innovation, qualifications of the investigator, and demonstrated use of one or more cores. The successful application will also have a demonstrated potential for NIH funding. A NIH-style biosketch with Other Support and a one-page outline of the budget must be included with the application. Approximately 6-10 investigators will be asked to complete the second level review process.
Second level review
Investigators with the highest rated applications in the first level review will be asked to submit full pilot project applications for review by the PAF program committee. This application will use PHS398 form (http://grants1.nih.gov/grants/funding/phs398/phs398.html) except that the project description (Sections A-D) is restricted to 5 pages. These applicants will also be requested to contact the Biostatistical/Bioinformatics Resource (BBR) for advice and input prior to submission.
Review of the Pilot and Feasibility Proposals
The PAF review committee will meet within one month of the receipt of final applications and will review all the applications. Applications will be scored on the 1-5 point NIH scale and recommendations for funding will be primarily based on these scores. Criteria for funding will include: 1) likelihood that the research effort will be productive and lead to NIH funding involving AKI; and 2) use of the core facilities provided by the P30. To permit full utilization of all the cores, funding considerations will also include an assessment of which core(s) will be utilized by the PAF application.
Scoring criteria:
Scoring will focus on three areas: i) qualifications of the principal investigator (and to a lesser extent, co-investigators) to lead the research effort toward NIH funding, (ii) quality of the research (scientific merit and innovation), and (iii) relevancy to the mission of the P30 and direct involvement of one or more of the cores in the research plan.
Proposals that foster collaborations within the UAB-UCSD O’Brien Center will be encouraged. Efforts will also be made to encourage applications from junior faculty, as well as women and minority investigators.
The reviewers will provide a concise, one-page written review of each application’s strengths and weaknesses, as well as recommendations for improvement. Each critique will be returned to the applicant. This peer review process is intended not only to identify the most meritorious proposals, but also to help enhance the scientific quality of applications not selected for funding.
Following the Pilot and Feasibility Studies Committee review meeting, the PAF Director will forward the funding recommendations to the Center Director, Co-Directors and Internal Advisory Committee for final decision. Three to four Pilot Studies will be funded per year, with a fifth designated as an alternate. The number may be lower based on the recommendations of the PAF Studies Committee, as well as programmatic considerations. However, we anticipate that through existing partnerships with the other Centers at UAB and UCSD, funding of additional pilot projects will be feasible.
Successful applicants will be required to submit a progress report at the end of the funding period. A second year of support is dependent on a competitive review of the progress made and resubmission of a research proposal.
Oversight and Review of Ongoing Pilot Studies
The Director of the PAF Program will provide scientific oversight of the Pilot Studies. It is anticipated that a significant number of Pilot Study awardees will be young investigators. Therefore, the Director will meet quarterly with each investigator - in person or by live videoconferences for investigators from the Extended Research Base - to review the project progress. This mechanism is designed to reduce problems encountered in the execution of the research plan and to facilitate advice and mentoring should difficulties arise. Funded junior investigators will be encouraged to have mentors and if not in place, the PAF Director will assist the investigator in identifying a mentor within his/her institution. We feel this is important not only in guidance and completion of the proposed research but especially for career development. The services of the BBR will also be available for consultation.
In certain circumstances, the Director of the PAF Program may recommend the termination of funding for a pilot study. This recommendation will be forwarded to the Center Director who will make the decision to terminate with the advice and consent of the Internal Advisory Committee. Reasons for early termination would include: 1) acquisition of extramural funding for the project; 2) evidence for duplicate funding; 3) determination that the project as designed is not feasible; 4) departure of the investigator from his/her current faculty position; 5) disapproval of the project by the IRB or IACUC. If sufficient funds remain and there is a meritorious project that was not funded in the previous cycle, then the funds will be awarded to that project. Otherwise, the funds will be distributed among the other awarded PAF projects if the principal investigators can justify the budget increase.
Programmatic Oversight of the Pilot and Feasibility Program
The Director of the PAF program will be responsible for obtaining written reports from the Pilot Study investigators at the end of the funding period. This outcome follow-up is designed to gauge the impact of the Pilot funding on new discoveries (including patents), publications, and extramural funding.
The Administrative Core will maintain all records pertinent to the Pilot and Feasibility studies, e.g. reviews, publications, and written progress reports. This Core will also provide fiscal oversight of the Pilot Studies.
The Internal and External Advisory Committees will review the quality and productivity of the PAF Program and its thematic direction annually.
Current Pilot Grant awardees:
PILOT PROJECT 1
Title: Oxidative modification of mitochondrial protein thiols during acute kidney injury
PI: Aimee Landar, Ph.D.
Assistant Professor, Department of Pathology, UAB
Summary:
Ischemia-reperfusion injury is a relatively common problem. Within the cell, one of the most sensitive targets of oxidative/nitrative stress is the mitochondrion. Mitochondrial perturbations result in impairment of ATP homeostasis, structural abnormalities and are the major source of reactive oxygen and nitrogen species (ROS/RNS) in other cells types. The mechanisms through which oxidative stress leads to renal injury are likely to involve post-translational modification of proteins, particularly the oxidation of protein thiols in the mitochondrion. In fact some changes in protein thiols have been identified in renal dysfunction, however, these studies did not analyze the thiol status in the mitochondrial proteome in a quantitative manner. These concepts are important because they are the first step in linking the post-translational modification of proteins to functional outcomes. The targets and molecular mechanisms that underlie ischemia/reperfusion injury in the kidney during transplantation are unknown and the focus of this proposal.
PILOT PROJECT 2
Title: Role of Caveolae in Acute Kidney Injury
PI: Hemal H. Patel, Ph.D.
Assistant Research Scientist, Department of Anesthesiology, UCSD
Summary:
Ischemia/reperfusion injury is a cause of acute renal failure that is associated with high morbidity and mortality. Ischemic preconditioning, a phenomenon whereby brief ischemic insults protect against subsequent more prolonged ischemic insults, has been described in many organs including the kidney. In multiple cell systems, the major source of damage during ischemia/reperfusion (I/R) injury appears to be the generation of reactive oxygen species (ROS). The resulting damage leads to necrosis and apoptosis. One of the major populations that is prone to I/R injury and acute renal failure is the aged population likely due to increased age related apoptosis and generation of ROS. Few studies have focused on the renal protective mechanisms or lack thereof in the aged population. The working hypothesis is that caveolae, membrane microdomains enriched in cholesterol and the structural proteins caveolins, act as a “sponge” to regulate the generation of ROS by virtue of close apposition to mitochondria and enrichment of reductive enzymes. Loss of caveolae may lead to the deleterious effects of aging inducing increased mitochondrial dysfunction. The specific aims to test this hypothesis are: Aim 1: Determine caveolae formation, enrichment of reductive enzymes in caveolae, apposition of caveolae-mitochondria and ROS generation in kidneys from young (6 months), mid-aged (16 months) and aged (20+ months) mice. Aim 2: Determine if renal preconditioning is absent in aged animals and animals that lack caveolin-1 expression. The insights gained from this preliminary work and more complete future investigations will have clinical implications for aged individuals and patients affected by AKI.
PILOT PROJECT 3
Title: p150/95-Dependent Regulation of Renal I/R Injury
PI: Bullard, Daniel C., Ph.D.
Associate Professor, Department of Genetics, UAB
Summary:
This application will address the novel hypothesis that p150/95 (CD11c/CD18 integrins) plays a role in ischemia-reperfusion (I/R) renal injury. Very little information is available regarding the function of p150/95 (CD11c/CD18) in the development of renal inflammation in the setting of AKI. p150/95, which also serves as a receptor for ICAM-1, is expressed on a number of different leukocyte subtypes, including resident dendritic cells that have been previously implicated in promoting kidney injury, suggesting this adhesion molecule, like LFA-1 and Mac-1 may also be important in the development of AKI. We recently analyzed CD11c mutant mice in a model of acute renal ischemia reperfusion (I/R) injury. Unlike other studies that have suggested that knockout of WBC ligands confer protection, the preliminary data show that the converse appears to be the case with CD11c/CD18: deletion caused a paradoxical worsening of ischemic acute kidney injury. To test this hypothesis two Aims are proposed. In aim 1, specific alterations in kidney cytokine and chemokine expression in CD11c mutant and control mice will be determined during I/R injury. In aim 2, the roles of p150/95 expression on different leukocyte subtypes in promoting severe renal I/R injury will be assessed. The studies should provide new insights into the role of inflammatory cells in renal injury. By demonstrating what accounts for the worsening of injury, new therapeutic options may emerge in the management of AKI related to I/R.
PILOT PROJECT 4
Title: Senescent/CKI Arrest and Dysfunction: A New Paradigm in AKI
PI: Satriano, Joseph, Ph.D.
Associate Research Scientist, Department of Medicine, UCSD
Summary: The investigator seeks to explore the potential role of altered cyclin dependent kinase expression, cell senescence, DNA damage, p27, and their roles in ischemic reperfusion (I/R) injury and long-term outcome following a bout of AKI. The project will test the hypothesis that the setting of increased oxidative stress, induction of chronic kidney injury, and shortening of telomere length observed in IRI would lead to induction of cellular senescence. Although this phenotypic change would affect kidney function, disease progression, and the susceptibility of future insults, characterization of this change has not yet been evaluated in AKI. The area of AKI leading to progressive chronic kidney disease is of obvious clinical relevance and this project may provide novel insights for the role of premature senescence in this process.
Educational and Enrichment Program
Seminar series
Link to NRTC and UCSD nephrology seminar schedule
Training Grants
UAB and UCSD have strong record of NIH-sponsored T32 training grants. The O’Brien Core Center leadership (Director, Associate Directors, Core Directors) contribute to multiple training grants at both institutions. Several of these T32 grants have particular relevance to AKI-related research:
1) A Training Program in Cellular Physiology (T32 DK07553; PI - DJ Benos, UAB)
2) Nephrology Training Grant (NIDDK T32 DK07671; PI: S Thomson, UCSD);
3) Basic Mechanisms of Lung Diseases (NHLBI T32 HL07553; PI - JL Yother, UAB);
4) Mechanisms of hypertension and cardiovascular diseases (5T32HL007457; PI - S Oparil, UAB);
5) UAB Clinical Research Training Program (NHLBI K30 HL04146).