CIRM: RFA 07-03 Summaries of Review Reports (Major Facilities Grant Application): FA1-00600-1

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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00600-1

Recommendation: Recommended for further consideration as a CIRM Center of Excellence
Element X Score: 81
Element Y Score: 85
Element Z Score: N/A
Use & Contribution Score: 83

Public Abstract (provided by applicant)

Facility

{REDACTED} proposes to develop a CIRM Major Facility to investigate the role of stem cells in aging and in the pathogenesis, diagnosis and treatment of age-related disease. A new building devoted to human embryonic stem cell (hESC) research will be constructed adjacent to space earmarked for our CIRM Shared Research Laboratory and Stem Cell Techniques Course. The project will be expedited by our recent experience completing a NCRR Center for Integrative Studies of Aging on time and within budget. The CIRM Major Facility will contain laboratories for 12 principal investigators (PIs) and space for cell culture, shared equipment and research cores. The cores will be devoted to cell sorting, imaging, genomics, proteomics, high-throughput screening (HTS), electrophysiology and bioinformatics/statistics, and will be fiscally separate satellites of existing, NIH-supported cores. The CIRM Major Facility will be closely integrated with our CIRM Shared Research Laboratory, which will house another 4 PIs. Core support within the Institute but outside the Facility will include the vivarium and the transgenic and animal-behavior cores.

Program

{REDACTED}’s stem-cell program is focused on understanding the role of stem cells in aging and age-related diseases and identifying ways in which stem-cell technology can used for diagnosis or treatment. The current program comprises both basic/discovery and preclinical/translational research. Basic/discovery hESC projects include studies of epigenetic control, programmed cell death, senescence, hypoxic regulation, IGF/TOR pathways, cell-cycle checkpoints, mitochondrial function, pluripotency factors and genome integrity. Preclinical/translational projects include studies of hESC-derived cells in animal models of Parkinson’s, Alzheimer’s and Huntington’s diseases, stroke and aging, as well as HTS for hESC-interacting factors.

Program Development

The proposed CIRM Major Facility will support expansion of {REDACTED}’s stem-cell research program to a total of 16 PIs engaged primarily or exclusively in stem-cell projects, accounting for about 40% of our faculty by 2011. The CIRM Major Facility will house 6 current PIs, 3 recruits from ongoing searches targeting diabetes, cardiovascular disease and motor neuron disease, and 3 future recruits prescribed by {REDACTED}’s strategic plan, while our CIRM Shared Research Laboratory will house 4 additional PIs. The CIRM Major Facility will also enhance the contributions of our CIRM Shared Research Laboratory and Stem Cell Techniques Course to the stem-cell community. Our hope is that collectively, these efforts will lead to the development of tools (hESC culture techniques, optimal hESC differentiation for transplantation, drug screens), diagnostics (markers of aging and age-related diseases) and therapies (drugs, transplantation strategies) for diseases associated with aging, including neurodegenerative disorders and cancer.

Statement of Benefit to California (provided by applicant)

The 2000 US Census showed that 10.6% of Californians were aged 65 or older and 1.3% were 85 or older. According to a 2003 special report from the California Policy Research Center on “The Growth and Aging of California’s Population”, the proportion of Californians aged 65 or older will increase to 20.5% over the next 50 years, and 4% will be 85 or older. As noted in the California Health and Human Services Agency’s 2003 Strategic Plan for an Aging California Population, many of these individuals can be expected to suffer from chronic diseases such as cancer and Alzheimer’s disease, so that a key element in preparing for the aging of California will be “developing new treatment modalities and medications that slow disease progression, improve treatment of symptoms, and/or reverse the course of disease”.

{REDACTED} is devoted to research on aging and age-related diseases. We propose to develop a CIRM Major Facility to investigate the role of stem cells in aging and in the pathogenesis, diagnosis and treatment of age-related disease. A new building devoted to human embryonic stem cell (hESC) research will be constructed adjacent to our CIRM Shared Research Laboratory and Stem Cell Techniques Course, and will contain laboratories for 12 principal investigators (PIs) and research cores. The CIRM Major Facility will be closely integrated with our CIRM Shared Research Laboratory, which will house another 4 PIs and additional cores.

The proposed CIRM Major Facility will support expansion of our stem-cell research program to a total of 16 PIs engaged primarily or exclusively in stem-cell projects, accounting for about 40% of our faculty by 2011. In addition to the areas listed above, ongoing or planned faculty searches are targeting diabetes, cardiovascular disease and motor neuron disease. The CIRM Major Facility will enhance the contributions of our CIRM Shared Research Laboratory and Stem Cell Techniques Course and help lead to the development of tools (hESC culture techniques, optimal hESC differentiation for transplantation, drug screens), diagnostics (markers of aging and age-related diseases) and therapies (drugs, transplantation) for diseases associated with aging.

Review Report

Executive Summary

In this application, the applicant institution proposes a new stem cell program focused on exploring the role of stem cells in aging, and extending pre-clinical studies on the use of stem cells to treat age-related diseases. This is a strong application with a well-defined focus on one particular disease area. A new building would house 12 principal investigators, hESC culture rooms, and several cores (i.e., fluorescence activated sorting, confocal and in vivo whole animal imaging, genomics, proteomics, high-throughput screening, electrophysiology, bioinformatics and statistics). The proposed facility will be merged with an already-awarded CIRM Shared Research Laboratory which will house 4 principal investigators (PIs) for a total of 16 stem cell programs. There are core facilities for a wide range of services.

The institution is dedicated to the study of aging and intends to devote 40% of its faculty and resources to stem cell research, which it considers to be appropriate for the importance of their research focus. A total of 18 investigators were named, 16 of which are PI’s. Major projects include genomic and proteomic studies of hESC differentiation, neural differentiation, senescence, and various mechanisms of differentiation and senescence. The faculty are very well-funded by NIH. They are clearly very committed to stem cell research; they already have a superb faculty and plan to recruit additional faculty in the coming year. They plan to complete the facility by mid-2010 if the funds are awarded in January 2009.

Element X consists of 13 science projects, six of which will be housed in the CIRM facility. The anchor of the program is an outstanding investigator from biotech, currently an Adjunct Professor at the institution, who plays a central role in several of the projects. Projects were solid and very well integrated. Element Y comprises 10 projects, six of them to be housed in the new facility. The faculty overlaps with the faculty in Element X, including the central PI mentioned in Element X. Several of the projects focus on developing disease models, particularly for neurodegenerative diseases. Reviewers found many of the projects innovative and highly relevant.

This is a well-written, well-thought out proposal highlighting strong science with tremendous institutional commitment. The projects are well-integrated and uniquely organized around the central theme of aging, although some of the projects are a little weaker than others. The only major concern brought up by the reviewers was the unclear affiliation of the central investigator who is cited on most of the highlighted projects. This PI has the most experience in ES cells in the group, plays a central role in several of the projects, and has a well-thought-out interaction throughout the proposal. However, the application did not clearly indicate whether this investigator would be moving to the institution or remain an adjunct professor. The lack of clarity regarding the status of this investigator was seen as a serious drawback to the application, and should be addressed as reviewers felt that it impacted the feasibility of the proposal. However, many panelists stated that they would cast their vote assuming that this PI would NOT join the institution on a full-time basis, stating that the application was strong enough without this investigator.

Reviewers highlighted the novel focus of the research (on aging). The investigators at the institution are outstanding and it was felt that they would make important contributions to the field. The proposal is well-integrated and well thought-out, and has tremendous institutional commitment.

Detailed Summary

Element X

Score: 81

SCIENTIFIC PROGRAM: In general, the quality of the scientific program is high. The project has substantial breadth and depth, excellent faculty, and a strong commitment on the part of the organization. Overall the projects are well integrated into one major theme (aging) and are put forward by excellent researchers; however, some of the projects are not particularly innovative, and there is very little ES cell experience at the institution. Six out of the 13 basic science projects will be housed directly in the new facility. These are generally the most senior and productive of the faculty. While the science is a little less risk-taking compared to the program housed outside of the facility, the scientific program is generally solid and well thought-out.

FORMAL INSTITUTIONAL COLLABORATIONS: The applicant institution has a number of well-documented collaborations with other top institutions in the area of stem cell research. Its core facilities will be used by these groups as well. However, most of the research interactions described in this proposal will be on campus.

CORE SERVICES: The application lists standard core services, all of which are already established and seem to be fully functional. In general, the requested core facilities are very reasonable and relevant to the proposed facility and research. There are a number of formal inter-institutional collaborations that are adequately documented, and these institutions will have access to the new facility’s cores. The core facilities are supported by experienced personnel and faculty.

The cores to be housed in the facility include:

Core A. hESC culture. Both NIH and non-NIH cell lines will be maintained.
Core B. hESC characterization. (e.g., karyotyping, qPCR of pluripotency markers, teratoma formation in vivo)
Core C. Fluorescence-activated cell sorting (FACS).
Core D. Imaging.
Core E. Genomics.
Core F. Proteomics.
Core G. High throughput screening.
Core H Electrophysiology.
Core I. Bioinformatics/statistics.

The cores to be housed outside the facility include a vivarium, a transgenics core, and an animal behavior facility (discussed in Element Y).

PLANS FOR GROWTH: The application lists an excellent plan for growth, and expressed dedication to human ES cell research and combining this with aging research. Five of the PI’s are now housed in an existing building. The institution will complete the CIRM shared research laboratory and stem cell core space in mid-2008. Three of the existing PIs will move into that space, and a fourth PI will join them, perhaps on a part-time basis although this was unclear. The cores will be placed in that space. Faculty searches have already begun in three targeted areas that are described in the proposal.

The institution anticipates completing the facility, if awarded January 2009, in mid-2010. They anticipate a total of 18 PI’s of which 10 are focused on Element X and 8 on Element Y with 3 secondaries in each. Six of the faculty will be housed in the CIRM facility and the remainder (12) will be located on campus. 15 of the 18 have tenure.

DISCUSSION: The investigators at the institution and in this Element are outstanding, and it was felt that they would make important contributions to the field. The proposal is well-integrated and well thought-out, and has tremendous institutional commitment. The building plan does not discuss how the facility would specifically address X and Y elements separately.

Element Y

Score: 85

SCIENTIFIC PROGRAM: The projects under Element Y are well thought-out and are highly relevant. Most of the 10 projects focus on neurodegenerative disorders, primarily ischemia, aging, Parkinson’s diseases, Alzheimer’s disease, and Huntington’s disease. Both in vivo and in vitro models will be used.

The projects include some very innovative proposals by newer faculty as well as thoughtful and important proposals by more experienced investigators. Several address the development of disease models (e.g., Parkinson’s disease and Huntington’s disease) and others the development of cellular therapies. A proposal for a high throughput screening of neurotoxins was a noted highlight of this section.

FORMAL INSTITUTIONAL COLLABORATIONS: There are some collaborations with other institutions but most of the important interactions are within the institution’s campus. One PI has a laboratory at a top collaborating institution.

CORE SERVICES: In addition to the standard core services described in Element X, the program will include a vivarium, a transgenics core, and an animal behavior core, all of which are already established and seem to be fully functional. These facilities are housed outside of the facility, but most of the investigators that are doing in vivo work will be outside of the facility as well. This is reasonable since faculty are all on the same campus and working closely with each other.

PLANS FOR GROWTH: Plans for growth for the X and Y element were described jointly, as the institution stated “we expect that most PIs will be involved in both basic/discovery and preclinical/translational hESC research.”

DISCUSSION: Again, reviewers highlighted the novel focus of the research (on aging). Many interesting projects were described in this section, although many of them were more basic than translational and some of them lacked creativity. The modest building plan does not discuss how the facility would specifically address X and Y elements, but appears to combine them. The institution is also planning cardiovascular and diabetes disease areas, for which they will recruit. The vivarium seems to be outside the facility but this was not necessarily a concern.

Use & Contribution

Score: 83

The application does not describe in detail the specifics of how the core facilities will be organized and physically arranged. Some of the core facilities will not be situated in the new CIRM Major Facility. According to the application, all the cores exist currently and Core A-D will be part of the CIRM Shared Research Laboratory for stem cell cores (that has already been funded) while satellites of Cores D-I will be in various places in the CIRM Major Facility. The salaries of personnel for the Core Facilities are supported by the institution, while investigators contribute a small percentage of their grant support for access to the cores. The institution has a strong record of providing core support to its investigators and this is clearly reflected in a number of NIH program and center grants that were awarded to them. So while the physical details of the core facilities were not provided, it is fair to say that it will be competently handled. The fact that all the facilities will be on one campus with laboratories in close proximity to each other also is reassuring. Finally, in several places, the application pointed out that the already-awarded CIRM shared laboratory will closely integrated into the new Major CIRM facility.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

Penhoet, Ed