COBRE Pilot Projects Program
The Pilot Projects Program will support innovative translational research from promising junior investigators (PJIs) or teams of researchers that have unique laboratory or clinical observations that require preliminary data to support competitive grant applications. This program builds upon the successes and experiences of the Pilot Projects of Phases I and II of the COBRE. The long-term goal is the expansion of the critical mass and skills of translational researchers who collaborate to move scientific observations from the laboratory to the clinic, and vice versa. We will select research proposals that expand our understanding of the mechanisms that initiate, promote or maintain chronic inflammation as a precursor or driver of disease, and test novel approaches that modulate inflammation as a means of preventing or treating diseases resulting from this process. The Phase III COBRE Pilot Projects Program will competitively select proposals to receive funding for one year, with a possible second year dependent upon satisfactory progress and the likelihood of external funding. We will consider funding PJIs who have a strong mentorship plan and have shown exceptional productivity, or teams of investigators proposing highly novel translational initiatives that may result in groundbreaking observations. This initiative builds upon our experience whereby novel observations by a team of COBRE researchers (junior and senior mentors) resulted in significant new funding, including an NIH Director’s Transformative Award in 2013. This success is in great part due to the integrated support program provided by the COBRE that includes discussion of the scientific concept, designing an appropriate experimental plan, access to state-of-the-art scientific cores, a critical review of the data, grant development, and administrative support. The COBRE leadership team will identify investigators who have an exciting, high quality research project and are most likely to be successful in producing high impact publications and grant proposals. The Pilot Projects Program will increase the number of trained translational researchers and research teams in Louisiana, and will strengthen cutting-edge research on inflammation-driven chronic diseases that are highly prevalent in our state and are a major cause of health disparities.
We will achieve our goals through the following Specific Aims:
Specific Aim 1. To provide funds and a strong mentoring environment to Promising Junior Investigators who study various aspects of inflammation, genetic regulation of inflammation and its effect on disease (initiation, development and outcome), with the goal of developing preliminary data that support the submission of competitive grants.
Specific Aim 2. To increase the number of “team-science” grants addressing inflammation and diseases by providing pilot funding to teams of investigators developing comprehensive multi-disciplinary projects.
Specific Aim 3. To support unique opportunities to translate laboratory findings into the clinic.
BACKGROUND AND SIGNIFICANCE
Significance: Training investigators who are able to translate results obtained in the laboratory into new diagnostic tools, new prevention strategies, and novel treatment of disease is essential to address the unique health problems that affect the large underserved minority populations of Louisiana. These investigators will be critical to the implementation of cutting-edge medicine that will improve health outcomes in the state of Louisiana. The Pilot Research Program will train young investigators and senior researchers who discover unique scientific findings and require support to move their observations into the clinical setting.
Team-Science Experience: Team-science collaborations have also been supported with Pilot Project Funding. These research opportunities were born from the presentation of data at the weekly “Work-in- progress” meeting. The open discussion and exchange of ideas resulted in highly innovated research project by teams of mentors and mentees that expanded the scope of this COBRE and created new funding that now supports our work. Examples of these are:
Inflammation, Obesity, and Asthma: Two Pilot Projects were initiated during the Phase I of this COBRE aimed at understanding the role of inflammatory mediators in patients with asthma and obesity, and the potential role of exercise and/or diet interventions. The preliminary data generated initially demonstrated a significant health disparity between African American and Caucasian patients. These data were significant enough to be included as part of a larger P20 multi-institutional grant the Dillard-LSUHSC Center for Minority Health and Health Disparities (P20MD004817) co-directed by Dr. John Estrada, and collaboration with the University of Alabama (U54MD008176).in which Dr. Jovanny Zabaleta, a Phase II PJI, is a project PI.
Pegylated–arginase-1 (PEG-Arg-1) to prevent Graft vs. Host disease (GVHD): Team-science between Paulo Rodriguez, PhD, Robert Emmons, MD (Ochsner Clinic) and Bruce Blazar, MD (a renowned bone marrow transplanter and Director of the CTSA at the University of Minnesota), showed that PEG-Arg-1 was able to inhibit T cells that cause graft vs host disease in an animal model of bone marrow transplantation. Continued work has started to study the effect of PEG-Arg-1 on T cells inducing GVHD obtained from patients. The initial data of this work was published and presented as a proposal for local funding, successfully receiving three years of funding from an Ochsner Cancer Research Program. This work is also being submitted as an R01 grant.
PEG-Arg-1 as a Novel Anti-viral Agent for Severe Viral Infections : Team-science between Timothy Foster, PhD, Paulo Rodriguez, PhD, and Augusto Ochoa, MD, began when Dr. Rodriguez, showed that this novel biopharmaceutical agent not only had anti-leukemic activity, but a dramatic anti-inflammatory effect. Dr. Foster hypothesized that if arginine depletion might be able to inhibit viral replication in infected cells and therefore could have potential applications as an anti-inflammatory agent with anti-viral properties. This hypothesis was tested in vitro and vivo in a rabbit model of severe viral keratoconjuntivitis with Herpes Simplex Virus. The results showed that PEG-Arg-1 completely inhibited viral replication and blocked the damaging inflammatory response. This novel and unexpected observation was proposed as a multidisciplinary project where Dr. Foster (a virologist), Dr. Rodriguez (an immunologist), and Dr. Ochoa (a clinician) co-authored a proposal entitled “Metabolic Approaches to Treat Severe Viral and Inflammatory Diseases”, which received a score of 1.5 and was one of ten proposals funded by the NIH Director’s Transformative Award in 2013 (R01-OD016990).
Experience of the Leadership Team. Dr. Augusto Ochoa, who is the PI of this COBRE program, will also serve as the leader of the Pilot Project Program. As the PI of the COBRE and the Pilot Programs for the last 10 years, he has gained critical experience with this type of initiative. In addition, he is the director for the Pilot Project Program of the Louisiana Clinical and Translational Science Center (LA CaTS), an IDeA grant funded two years ago at the Pennington Research Center of LSU in Baton Rouge, LA. Dr. Ochoa modeled LA CaTS Pilot Projects Program based on the experiences from this COBRE. The LA CaTS IDeA has had two funding cycles for pilot projects and one round of team-science multi-institutional grant awards. Dr. Ochoa has led these initiatives, from writing the RFA announcement, to coordinating and conducting the reviews and selection of the projects, as well as tracking scientific and career development progress of the PJIs. Therefore, Dr. Ochoa and his team have the expertise to ensure that the Pilot Project Program in this COBRE will continue to be successful.
Two experienced co-leaders will join Dr. Ochoa: Dr. Lucio Miele, senior advisor for the Translational Genomics Core of this COBRE, director for inter-institutional research programs at the LSU Cancer Center and previous director of the Cancer Institute at the University of Mississippi; and Dr. John Estrada, director of the Mentoring Program of this COBRE for past 10 years and director for Community Outreach Initiatives and Health Disparities research of the LSU Cancer Center. Dr. Miele is an expert in cancer biology and cancer genetics, with special expertise in Notch signaling, not only as a promoter of carcinogenic transformation, but also as a regulator of inflammation in the tumor microenvironment. Dr. Miele has mentored 36 post-doctoral, medical, undergraduate and graduate students, as well as six early-stage investigators throughout his lengthy career.
Dr. Miele will play an essential role in the selection of promising projects in the Pilot Projects Program. He has chaired DOD study sections reviewing IDeA and career development (fellowship) grants for the past 6 years, and he was a member of an NCI Fellowship study section last year. For the past 15 years, Dr. Miele has served as a reviewer on numerous NIH study sections including R01s (ET-1, DMP, TME, BMCT), P01s (Clinical Sciences), and CTSAs. Dr. Estrada was the director of the Mentorship and Faculty Development Core during Phase I and II of this COBRE, and gained tremendous expertise in mentoring foreign-trained junior faculty. Additionally, he is an expert in the social and biological determinants of health disparities, a subject that he introduced into the research projects supported by this COBRE. This leadership team will ensure that: the program is implemented in a timely manner; the projects selected for review are the most promising and most likely to deliver results; the selected reviewers are balanced in terms of their expertise; and the selected grantees of the Pilot Projects have optimal scientific and mentoring support to optimize their development as independent scientists and productive teams in science.
Plan for Soliciting Proposals, Prioritization, and Review of Research Projects and Performance: A request for COBRE Pilot Project applications (RFA) will be advertised annually with a due date of March 1, followed by review, selection, and final evaluation by the EAB. We plan to complete this process and select the highest scoring projects for a start date of July 1, which coincides with the start of the institutional fiscal year and budget period for this COBRE. COBRE Pilot Project proposals will be solicited using standard means of communication, posting the RFA and grant submission process (guidelines, eligibility requirements, application instructions) through: the LSUHSC's Office of Research Services funding announcement system; the LSUHSC campus and Inter-University email, the Cancer Center e-mail list- serve; the Louisiana INBRE and COBRE websites, and the state-wide LA CaTS program. These methods for soliciting proposals were established by the LSUHSC administration.
The selection proceeds as follows:
- A Request for Applications (RFA) announcement will be sent out and posted as described above. The RFA will request an initial Letter of Intent to Apply (LOI) to be sent within three weeks of the announcement released in January of each year.
- The LOIs will be screened by the leadership team to ensure that they meet the requirements.
- Selected LOIs will be invited to send in a full application within a 6 weeks of receipt of the invitation
- Reviewers from local institutions – LSU Health Sciences Center New Orleans; Pennington Research Center and LSU Main Campus - Baton Rouge; Tulane Medical Center (School of Medicine and School of Public Health) and Children’s Hospital Research Institute – will be invited according to the expertise needed to evaluate the proposals.
- Each application will be sent to 3 reviewers electronically with a request to review in 4 weeks of receipt (maximum of 3 applications per reviewer).
- Written reviews and scores will follow the NIH review criteria and scoring system (1-9). Once the reviews are received, a teleconference with the reviewers will be scheduled for discussion and selection of the highest scoring applications.
- The highest scoring proposals will be sent to the External Advisory Board Members for their review and final approval.
- Final scoring tabulations will be completed by the COBRE coordinator and the PI.
- Applicants selected for funding will be notified by mail. Just-in-time (JIT) information will be requested, including updated and approved IBC, IRB and/or IACUC protocols.
- Final applications and regulatory protocols will be submitted to the NIGMS program official and grants manager for review and approval to begin the new projects.
- Grantees will meet with the steering committee to present their proposal and discuss the experimental design of the project, the planned use of COBRE core facilities, and the timelines for the scope of work. This will help investigators to optimize the productivity of their project.
- Grantees will give a 20-minute presentation of their proposal at the Work-in-Progress bi-weekly meeting prior to the beginning of their project and at least twice a year, thereafter, to evaluate progress.
- Applications for a second year of funding will be considered only after the completion of 9 months of work and only if there has been significant productivity towards the goals proposed.
- Successful researchers will continue to receive extramural grant submission support by the Grants Program of this COBRE, even after the completion of their Pilot Project.
- Attachment 1 provides an example of a request for applications that our COBRE will use to solicit Pilot Project applications.
Solicitation and Guidelines for Submission of Proposals: Applications for a COBRE Pilot Project by Promising Junior Investigators will follow a similar format and guidelines as required for an NIH R21 application. The application must include the following components:
- Description of the project (Abstract, NIH form).
- Research Strategy (6 pages maximum, excluding references).
- Specific Aims (1 page).
- Significance and Innovation (1/2 page). Emphasize how the question(s) being studied relate to the overall theme of the COBRE, i.e. the role of inflammation in the development of disease, and how the knowledge derived might translate to patient care.
- Preliminary Data (1 page). Present any available data in support of the hypothesis to be tested, or provide the rationale for changing research direction based on findings from other areas of research.
- Experimental Methods and Anticipated Results (3 pages). Describe the overall strategy and methodology, including use of COBRE Core Facilities, and analyses that will accomplish the specific aims of the project and describe anticipated results. Reviewers will pay close attention to pitfalls and alternate plans described in this section. If the applicant has current funding, the research plan must justify the request for additional funding by demonstrating a clear divergence in scientific and financial overlap from this research work.
- Plans and timeline for submission of a national grant application and publications (1/2 page).
- Biographical sketch following the 4-page NIH format for applicant and potential co-investigator(s).
- Budget: NIH forms, including budget justification.
- Vertebrate animal and human subjects sections including targeted enrollment tables, inclusion of women and minorities, and inclusion of children (NIH forms). Prior to grant award notification, IACUC, IBC, and/or IRB regulatory approvals will be required.
PJIs will be required to have a dedicated scientific mentor with a clear description of the mentor’s role, and a mentoring plan presented by the mentor. The PJI and the mentor will be asked to discuss the proposed project with the COBRE leadership team prior to the submission of their application. This will provide an opportunity to identify potential issues prior to the investigator submitting an application, and will increase the opportunity for successful completion of the proposed project.
For Team-Research Proposals, we will allow for three additional pages of preliminary data given that each participating investigator may be providing distinct expertise and information required for the full application. We will require a management plan and conflict resolution section to ensure that any issues that may arise among the researchers are rapidly addressed with the COBRE PI. The remainder of the proposal will remain the same.
Prioritization of Proposals: Proposals that are consistent with the theme of “Inflammation and Disease” will have first priority in the review process. These include, but are not limited to, diseases that promote cancer development, such as viral or bacterial (H. pylori) infections, obesity, and oncogenic mutations, or environmental agents that cause tissue damage and induce a chronic inflammatory response. We also will preferentially support research proposals addressing the differences in the regulation of inflammation among different racial groups as possible biological contributing factors underlying health disparities in various diseases. Specifically, we are most interested in understanding cancer precursor conditions that disproportionately affect the populations of Louisiana and the Gulf Coast including:
- HIV: Louisiana has the first (Baton Rouge) and fourth (New Orleans) cities with the highest incidence of HIV infection in the USA.
- HPV: Louisiana has one of the lowest vaccination rates in the country, and the efficacy of vaccination appears to be lower in African American women.
- Polyomaviruses: These viruses are increasingly associated with various tumors including common cancers such as colorectal carcinoma, and rare tumors such as Merkel cell carcinoma (associated with immunosuppression and sun exposure).
- H. pylori: Louisiana has one of the highest rates of stomach cancer in the US, particularly among the African American population.
- Obesity: Louisiana has the highest prevalence of obesity in the nation and therefore studying the biological basis of this pro-inflammatory condition is of great importance. In fact, obesity is considered one of the most prevalent preventable conditions shown to promote multiple chronic inflammatory diseases including certain forms of cancer.
- Environmental contaminants: Contaminants increase oxidative damage of tissues and promote oncogenic mutations as well as a micro-environmental inflammatory environment that supports cancer progression. These include environmental contaminants such as tobacco smoke, oil derivatives (from the frequent oil spills in our region), and natural radiation.
- Other chronic inflammatory diseases: Other chronic inflammatory conditions that have not necessarily been linked to cancer will be considered as potential research topics for support by the Pilot Project Program.
Review of Research Proposals: The Pilot Project Program Leaders, Drs. Ochoa, Miele and Estrada will manage the review process. All have extensive experience as reviewers of intra- and extra-mural grant applications, NIH grants, program projects, and site visits. All applications will also be reviewed and discussed by the Administrative Core for: completeness; current/past funding of the applicant; potential scientific overlap with other ongoing funded projects; and overall adherence to the mission of the Pilot Project program, which is to investigate a novel research idea in the broad area of inflammation and disease. Based on prior experience from Phase I and Phase 2, we anticipate receiving between 10-12 applications per year. Each application will have three reviewers including an external scientific reviewer unrelated to this COBRE, a member of the External Advisory Board and one member of the Steering Committee. The members of the External Advisory Board (EAB) are each internationally recognized investigators in inflammation, immunology, cancer, viral diseases, translational research, and bioinformatics. They are highly experienced in the review of local, state, and national grant applications, and two of them have participated in the review of Pilot Projects during Phase I and Phase II. The review panel is highly qualified to evaluate Phase Ill Pilot Project applications.
The review process will follow the same format and scoring as an NIH grant review. The criteria for evaluation will include: 1) scientific merit and significance; 2) novelty/impact of the study and association with the scientific themes of inflammation and disease; 3) qualifications and productivity of the applicant; 4) research plan proposed; 5) potential for translational or clinical research; 6) use of COBRE cores; and 7) potential for producing data that supports the submission of competitive extramural applications. Team-research projects will be evaluated also for integration, as defined in program project grants. The reviewers will complete the reviews within four weeks, after which the feedback will be compiled and a conference call will be arranged between the Pilot Program Leaders and the reviewers. Recommendation for pilot funding will be made based on application score and availability of annual funds. We anticipate that 3-4 highly meritorious projects will be selected for support. Prior to final selection, the highest scoring proposals will be sent to the EAB for approval. The top 3-4 applications from individual PJIs will be supported at $50,000 per year and one team- science project with two or more investigators will be supported at $100,000. Funding can potentially be renewable for a second year (2-year maximum), contingent upon demonstration of significant research accomplishments described in the quarterly “Work-in-Progress” presentations and the nine month progress report. Funding will be implemented and managed through the COBRE Administrative Core. Principal Investigators of proposals that are not selected for funding will receive a copy of the feedback to provide information that may help improve a future application.
Assurance of Compliance with Applicable Federal Policies and Guidelines for Research: All projects selected for funding will be required to provide institutional evidence that the PI has obtained all necessary approvals for animal studies by the Institutional Animal Care and Use Committee (IACUC) and Institutional Biosafety Committee (IBC) and/or the Institutional Review Board (IRB) for studies involving human subjects or human tissue. Prior to release of funding, the PI will also demonstrate compliance with other regulatory guidelines, including inspection approvals for laboratory safety, biohazards, radiation, etc.