Pilot/Feasibility (P/F) Project Program
Introduction and Goals
The Pilot/Feasibility (P/F) Project Program is a magnet that pulls investigators into the Liver Center and has helped sustain a robust cadre of investigators in the Liver Center over the last 20 years. The emphasis has been to fund young investigators, who are more likely to stay in digestive disease research if their P/F project is successful. The research potential of P/F project holders is markedly enhanced by the Core facilities of the Liver Center, which enable investigators to utilize research methodology that would otherwise be unavailable or unaffordable, and an Enrichment Program that has promoted numerous collaborations.
Goals of the P/F Project Program are to:
- Attract and support talented young investigators to work in liver disease-related research,
- Provide junior faculty with support and mentoring that will allow them to generate preliminary data for external funding,
- Facilitate collaborations between members of the liver center and established investigators in other fields,
- Encourage investigators to re-direct their science to a digestive disease related area.
Laurie DeLeve, M.D., Ph.D. (firstname.lastname@example.org) directs the P/F Project Program by annually announcing and actively soliciting potential applicants. She screens letters-of-intent with Dr. Andrew Stolz and Dr. Anisa Shaker, reviews all submitted applications to ensure completeness, assigns applications to the External Advisory Board for review, communicates External Advisory Board findings to applicants, and monitors submission of progress reports and progress made.
Research Strategy and Management of the P/F Project Program
All USC faculty members with a research project may apply for P/F project grant; senior fellows with a formal commitment for a faculty position are also eligible. The three categories of eligibility for the applicants are: Category 1: new investigators who are the principal investigator on a project and who do not have external funding; Category 2: established investigators in fields other than digestive diseases, who are interested in redirecting work and expertise to digestive disease; and Category 3: established investigators in digestive disease who wish to make a major shift in emphasis (e.g., intestine to liver). Category 1 applicants may be K grant awardees if the P/F project grant expands the scope of the work included in the K award; AASLD Liver Scholars and local foundation awardees are eligible under the same limitations. Applications for category 3 are the most closely scrutinized to ensure that funding of the project will fit the Center’s goals for an established investigator, i.e. retaining the investigator in digestive disease research or fostering new collaborations with center members. Among the 15 investigators funded in the current cycle, 14 investigators were eligible in category 1 and 1 investigator was eligible in category 2.
The topic of the application must be related to digestive diseases and preferably be consistent with the 4 Themes of the Research Base, which are: (1) Viral Hepatitis and Hepatocellular Carcinoma; (2) Steatohepatitis and Fibrosis; (3) Liver Injury: Hepatotoxicity, (Inflammation, Signal Transduction, Free Radical/Oxidative Stress) and Mitochondrial Pathobiology; and (4) Repair, Regenerative Medicine and Developmental Biology.
Solicitation and Review of Applications
During the last cycle we have broadened our outreach to solicit letters of intent. In late October/early November we disseminate the call for letters of intent by announcements in the two USC Health Science campus weekly newspapers, by inclusion in a weekly research e-newsletter circulated to all USC investigators on the Health Science Campus, Childrens Hospital of Los Angeles, and University Park Campus, by email to all Health Science Campus faculty, and by posting announcements in all research buildings on the USC Health Science Campus and at Childrens Hospital of Los Angeles. In addition, the Executive Committee identifies potential candidates. Information about the P/F Project Program and the application process will be posted on the Liver Center website.
Table 1 presents the timetable for solicitation of letters of intent and schedule of the review process. In late October or early November a call for letters-of-intent goes out that states that awards are available for projects in the field of liver and digestive tract function and that describes eligibility categories for investigators and Center Themes (see attached announcement for 2014 at the end). The announcement requests submission of letters-of-intent by mid-December that include: 1) contact information; 2) one paragraph with a project title, aims, rationale and the general methodological approach for the project; 3) one paragraph that states the eligibility category and the relationship to the Center Themes. Applicants are requested to submit the letter-of-intent, an NIH biographical sketch and other support. The announcement will state that minorities and women are encouraged to apply and that letters of intent should indicate whether the applicant is a minority or a woman. Dr. DeLeve’s telephone number and email are provided and potential applicants are encouraged to contact Dr. DeLeve for further information. The letters-of-intent are reviewed in December by Drs. DeLeve, Stolz and Shaker to be sure the applicants are eligible and that the projects fit within the research interests of the Themes. All non-eligible candidates receive an email to describe the reason the application does not fit criteria. All appropriate candidates are asked to submit a full application that includes a face page, abstract, biosketch, other support, budget, plus justification and a maximum 10 page research plan with appropriate Vivarium and/or IRB approval (or pending approval), a resource sharing plan, and for clinical research a planned enrollment report by late February. The instructions will indicate that proposals must include sample size calculations and/or calculations of numbers of animals needed that are justified statistically. Applicants seeking an additional year of funding also need to include a progress report of no more than 5 pages. The process has evolved from paper applications to electronic submissions and currently all applications are sent by email to the External Advisory Board 4-6 weeks before the Annual Symposium and meeting of the External Advisory Board. A primary and secondary reviewer from the External Advisory Board is assigned to each application and the reviewers submit a one page written critique. The applications are distributed according to the areas of expertise of the External Advisory Board and each Board member is primary reviewer of 2-3 applications and secondary reviewer of 2-3 applications. External Advisory Board members are encouraged to read all the applications. Although this has not yet occurred, but if there may not be the appropriate expertise on the External Advisory Board to review a particular application, then an outside referee would be asked to provide a written critique of the application. The overall impact of the proposal is scored between 10 and 90, with a cutoff of 30 being within the potentially fundable range.
Table 1 – Timetable for solicitation of letters of intent and the timing of the review process
|Call for letters of intent: late October/early November|
|Deadline for letters of intent: early December|
|Deadline for full proposals from new applicants/progress reports from current P/F holders: early January|
|Review of proposals annual symposium: early March|
|Funding: early April|
|SUMMER FUNDING CYCLE|
|Call for letters of intent: July|
|Deadline for letters of intent: August|
|Deadline for full proposals from new applicants: September|
|Review of by Advisory Board: October|
In 3 of the previous 6 years (2010, 2012, 2013), we have had a second round of funding in the summer. The process for reviewing these applications is the same as described above, except that the review does not include a face-to-face meeting of the Advisory Board. 8 applications were funded during the summer review round. Table 2 lists the numbers of letters-of-intent, completed applications, and funded applications received during the current cycle, between 2009 and 2014.
Each investigator who has submitted a new P/F grant application presents a 15 minute overview of the proposal at the Annual Symposium and answers questions for 10 minutes. All investigators who have had P/F funding that year present a 30-minute progress report and answer questions for 10 minutes. These presentations provide invaluable input to the investigators and provide the External Advisory Board the opportunity to gauge the strengths and weaknesses of the investigators and to better understand the proposals.
At the end of the day of the Annual Symposium, the External Advisory Board, Dr. DeLeve and the Center Administrator meet to discuss the applications. The Chairman of the External Advisory Board, Dr. Wolkoff, chairs the session in the same fashion as an NIH Study section, the Center Administrator records the minutes, and Dr. DeLeve is present to provide the Advisory Board with any additional information they might require on the applicants and to hear the discussion. During the meeting, the reviewers provide their scores, then the primary reviewer describes the projects and presents a critique, followed by the critique from the secondary reviewer. Applications are judged based on eligibility of the investigator, merits of the project, relevance to the Themes and Goals of the Liver Center, and the likelihood that the project will develop into a successful application for external funding. The Board members discuss the project and each Board member provides his/her score, which must fall between those of the two reviewers. All meritorious grants are ranked based on the scores and the Board reviews the rank list to make sure it reflects their relative levels of enthusiasm. After the meeting Dr. DeLeve, P/F Project Program Director, and Dr. Kaplowitz, the Center Director review the rank list, examine the budgets of the top ranked projects, and allocate the available funds according to the needs of the projects. The Executive Committee then ratifies the final decision. If all available funds are not allocated due to the applications not meeting the funding threshold (overall impact score of 30), a second, i.e. summer round is initiated. This procedure insures that only the most meritorious projects are funded.
Within a few days of the External Advisory Board meeting, applicants receive a notice of award or are informed that their project will not be funded. All applicants receive written copies of the reviewer’s critiques that provide constructive criticism and suggestions.
The reviews and the questions and comments provided during their presentations at the Annual Symposium provide a comprehensive process that is very helpful to the investigators. Unsuccessful applicants with projects that fall within the scope of the Liver Center are encouraged to revise and resubmit the next year, if still eligible.
Second year of P/F project holders may be awarded competitively, but a 3rd year of funding would only occur on extremely rare and highly meritorious occasions (none in the current cycle).
Table 2. Summary of Pilot/Feasibility Project Program Activity During Current Cycle
|Year||Letters-of-Intent||Completed Applications||Funded applications|
Description of Individual P/F Projects from most recent funded group
|Current funded projects|
1. Title: SNP Modeling with iPS-derived Hepatocytes for Non-Alcoholic Steatohepatitis Study
Principal Investigator: Toshio Miki, MD, PhD, Broad/CIRM Stem Cell Center
Eligibility Category: Category 1/New Investigator
Relationship to Center Themes: Theme 4: Repair, Regenerative Medicine and Developmental Biology (according to the new organization of Themes)
Project period: 4/14-3/15
Abstract of the Project: Human induced pluripotent stem cells (iPSCs) have been proposed as a powerful and efficient tool for liver disease studies for disease modeling, drug discovery, and cell therapy. We propose a novel approach to utilize the human iPSCs for studying non-alcoholic steatohepatitis (NASH). NASH is diagnosed in about 10-30% of all non-alcoholic fatty liver disease (NAFLD) patients. The discrepancy on NAFLD to NASH progression has been considered due to multiple genetic factors. Recent advancement of genome-wide association studies identified several single-nucleotide polymorphisms (SNPs) that are responsible for the progression of NASH, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3). However, limited supply of human hepatocyte and lack of appropriate in vitro models prohibit further analyses to elucidate the complicated interaction of SNPs and NASH progression without avoiding influences of environment and patients’ lifestyle differences. Our overall goal of the project is to elucidate the mechanism of pathogenic impact driven by genetic differences on NASH progression. We focus on answering two fundamental questions; (1) what is the mechanism of liver fat accumulation in the PNPLA3/I148M SNP cells, and (2) how does the PNPLA3/I148M SNP cause liver inflammation? To elucidate mechanism of intracellular pathogenic events under physiological condition, we propose to using PNPLA3/I148M SNP introduced human cell models.
Proposed core usage: CSC, AMI (Seahorse and HPLC), CTI, LH
2. Title: Notch reprograms metabolism to facilitate macrophage M1 activation
Principal Investigator: Jun Xu, MD, PhD, Department of Pathology
Eligibility Category: Category 1/New Investigator
Relationship to Center Themes: Theme 3: Liver injury (as per the new organization of Themes)
Project period: 10/13-3/15
Abstract of the Project: Macrophage (Mac) proinflammatory (M1) activation is a key pathogenic event of LPS-induced liver injury such as steatohepatitis and fulminant hepatitis. In particular, the M1 gene Nos2 is implicated in nitrosative stress, mitochondrial dysfunction, and hepatocyte damage. Our preliminary studies indicate Notch is a potential regulator of Mac metabolism and M1 activation. In M1 Mac isolated from a ASH mouse model or produced by LPS-treated Raw264.7 cells, the protein levels of Notch1 intracellular domain (NICD1) are increased, indicating Notch activation. Notch inhibitor DAPT abrogates M1 and Notch1 gene induction in these cells. NICD1 is enriched at the CSL/NICD site of the Nos2 promoter, and the LPS-induced Nos2 promoter activity is suppressed by DAPT, suggesting direct Nos2 activation by NICD1. The M1 Mac have increased glycolytic flux to the TCA cycle, mitochondrial respiration (OXPHOS), and mitochondrial ROS (mtROS), all of which are attenuated with DAPT. DAPT, glycolytic inhibitor 2-deoxyglucose, and mtROS specific scavenger MitoQ attenuate expression of Nos2 and other M1 genes, suggesting that mtROS generated by Notch-induced mitochondrial metabolism promotes Nos2 activation. LPS causes NICD1 translocation to mitochondria and binding to the mtDNA D-loop, which comprises the promoters of the mitochondrial genome. Systemic administration of DAPT attenuates NICD1 and NOS2 upregulation and hepatocellular inflammation in the ASH mice. Based on these findings, we propose the novel hypothesis that Notch mediates M1 Nos2 gene activation by directly stimulating Nos2 transcription and by augmenting this effect via mtROS generated by Notch-mediated induction of mtDNA-coded respiratory complex genes and mitochondrial OXPHOS activity. We will test this hypothesis with following two specific aims. (1) To identify NICD1-target genes responsible for increased mitochondrial glucose metabolism, OXPHOS, and mtROS generation. (2) To determine how mtROS augments Notch-driven Nos2 transcription. These studies will extend our understanding of the cellular and molecular events responsible for the LPS-induced liver injury and will identify potential therapeutic targets for the disease.
3. Title: Role of TET-mediated DNA demethylation in nonalcoholic steatohepatitis
Principal Investigator: Douglas Feldman, PhD, Department of Pathology
Eligibility Category: Category 1/New Investigator
Relationship to Center Themes: Theme 2: Steatohepatitis
Project period: 10/13-3/15
Abstract of the project: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide in both adults and children and can progress to the more severe and clinically intractable variant nonalcoholic steatohepatitis (NASH), leading to cirrhosis and liver failure. Recent molecular analysis of liver tissues isolated from NASH patients has revealed a striking, genome-wide depletion of DNA methylation at the C5-position of cytosine (5mC), a stable epigenetic mark functionally associated with the formation of repressive chromatin structure and gene silencing. The genome-wide depletion of 5mC in NASH correlates with disease-specific gene expression signature and disease severity, suggesting that changes in the cellular epigenetic status may underlie individual susceptibilities to this disease. However, the molecular basis for DNA demethylation in NASH-affected hepatocytes is poorly understood. The three members of the TET family of DNA-binding proteins (TET1/2/3) associate directly with CpG dinucleotides through their DNA-binding CXXC domains and catalyze the oxidative demethylation of 5mC, raising the possibility that excessive DNA demethylation observed in NASH may occur by a TET-dependent mechanism. Furthermore, we have recently identified the Cove protein as a ‘reader’ of 5hmC and demonstrated that it both maintains 5hmC levels and acts to stabilize chromatin-bound TET1. Interestingly, the expression of Tet1/2 and Cove mRNA are strongly induced in mouse livers following long-term high-fat or alcohol diets. Based on our findings, we hypothesize that TET-catalyzed formation of 5hmC promotes the loss of DNA methylation associated with aberrant gene expression and progression to NASH. Herein, we propose to rigorously evaluate this hypothesis and to examine the function of TET in NASH pathogenesis both in vitro and in vivo using mouse genetic models. We will additionally examine the clinical relevance of TET oxygenases in NASH disease progression using liver biopsy specimens from control and NASH patients.
Pilot/Feasibility Projects Awarded by RCLD (2004-2014)
Annual Announcement for Most Recent Round of P/F Project Program
Annual Announcement for Upcoming Round of P/F Project Program
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