General Information Applicable to All RFAs
Questions Specific to RFA-GM-10-007 Consortia for High-Throughput-Enabled Biology Partnerships (U01)
General Information Applicable to All RFAs
RFA-GM-10-005 Centers for High-Throughput Structure Determination (U54)
RFA-GM-10-006 Centers for Membrane Protein Structure Determination (U54)
RFA-GM-10-007 Consortia for High-Throughput-Enabled Structural Biology Partnerships (U01)
Q. Where can I find background information for PSI:Biology?
A. Background Information on PSI:Biology is at:
http://www.nigms.nih.gov/Initiatives/PSI/psi_biology/
http://www.nigms.nih.gov/Initiatives/PSI/psi_biology/psibiology_funding.htm
A workshop, "Future of NIGMS Structural Genomics Initiatives," was held in December, 2008, that helped establish the new direction of the PSI. The workshop summary is posted on the NIGMS Web site at http://www.nigms.nih.gov/About/Council/FutureStructuralGenomicsInitiatives.htm. You can find the workshop’s report at http://www.nigms.nih.gov/News/Reports/FutureSGMeeting102008.htm.
Q. What are the other components of the PSI:Biology Network and when will they be announced?
A. Program Announcements for Technology Development for Protein Modeling including Program Projects (P01) and Individual Grants (R01) and Technology Development for High Throughput Structural Biology Research including Program Projects (P01) and Individual Grants (R01) will be published in fall 2009 for planned receipt dates in February 2010.
Eligibility
Q. May industry participate?
A. Industrial applications and collaborations are permitted as long as all of the participating scientists understand and agree with the goals described in the RFA. In addition to the overall goals of high-throughput structural biology, the RFA requires that information and results be made public and protein structures be deposited in the Protein Data Bank and other databases in a timely manner.
Q. May foreign institutions apply?
A. Non-U.S. institutions may not apply for any of the RFAs, but they may receive subcontracts as components of the research centers and partnerships. Details on the NIH policy on foreign grants are given at http://www3.od.nih.gov/oma/manualchapters/grants/54104/
Q. Can an investigator be a PI or Co-PI or otherwise be a member of a HT-Center (U54) proposal and also be a Co-PI or otherwise participate in a Partnership (U01) proposal?
A. Yes. This is permissible. However, one cannot be the lead PI of an HT-Center and the lead PI of a Partnership.
Q. Can an investigator participate in more than one Partnership (U01) proposal?
A. Yes. This is permissible. However, one should bear in mind that you will in effect be competing with yourself.
Application
Q. Is the receipt date for applications October 9 or October 28?
A. It’s October 28. The original receipt date was extended. For details, see
http://grants.nih.gov/grants/guide/notice-files/NOT-GM-09-026.html.
Q. Is there a special application form?
A. No. The standard PHS 398 form http://grants.nih.gov/grants/funding/phs398/phs398.html should be used in response to all three of the RFAs, but the special application requirements described in each RFA must be carefully observed.
Q. Are applications restricted to current PSI-supported investigators?
A. No. The RFAs are open to all eligible applicants.
Q. May NIH staff assist an investigator in planning a project or finding collaborators?
A. No. NIH staff may provide background information and respond to questions about the PSI:Biology program and RFAs, but staff members may not participate in planning a project or application.
Q. May an investigator apply for more than one of the RFAs?
A. No. An investigator may not serve as the primary (or contact) PI on an application in response to more than one of the RFAs. However, an investigator may serve as the primary PI on a center application and as a participating investigator or subproject investigator on a partnership application.
Q. What are the page limits?
A. The overall application for center grant (U54) applications should not exceed 50 pages for the Research Plan Sections - Specific Aims, Background, Preliminary Results and Research Plan. The corresponding limit for partnership (U01) applications is 25 pages. See the RFAs for detailed contents.
Q. Are the management, administration and direction of the centers and partnerships of major importance?
A. Yes. Each center and partnership must have an organized and well-developed plan for management, administration and direction, as well as appropriate resources and staff.
Q. What are the current NIH guidelines for investigators regarding intellectual property issues?
A. Guidance for extramural investigators regarding the use and exchange of "research tools" is on the NIH Web site at http://www.nih.gov/od/ott/RTguide.htm. Applicants should develop plans for free and open access to results and information as well as the timely deposition and release of coordinates in the Protein Data Bank.
Q. What are the Cooperative Agreement Terms and Conditions of Award and why should I read them before I apply?
A. The Cooperative Agreement Terms and Conditions of Award lay out the management processes under which the entire PSI:Biology initiative will operate. It is important for applicants to know what they will be required to do and to include in their application plans that show how they will fulfill their responsibilities.
Q. How will multiple principal investigators be represented on the PSI:Biology Network Steering Committee?
A. Each funded U01 project will be allowed one representative on the Steering Committee; this representative will be determined by the investigators.
Review and Funding
Q. How will the PSI:Biology research center applications be reviewed?
A. The applications will be reviewed by the NIGMS/NIH peer review system. The Office of Scientific Review, NIGMS, will convene a panel (or panels) of reviewers.
Q. Are site visits planned for these applications?
A. Site visits are not planned at this time; while selected site visits could be performed as part of the reviews, they would depend on constraints on timing, NIH staff and resources. Applicants should present a complete, well-justified proposal and not assume that site visits will occur.
Q. Will NIH accept supplementary information following the submission? If so, what are the acceptable dates?
A. This is up to the Office of Scientific Review, NIGMS, and will be communicated to applicants once the applications are received. Typically, NIH accepts brief updates to publication information (submitted now in press, in press now accepted, etc.) and very brief updates of key preliminary results. However, plan on sending a complete and thorough application. Check with the SRO before sending additional material.
Q. When will the reviews take place?
A. The first level of peer review will likely occur in February or March 2010. The second level of review by the National Advisory General Medical Sciences Council will take place in May 2010.
Q. When will awards be made?
A. We plan to make awards by July 1, 2010.
Q. How will funding decisions be made?
A. NIH staff will make these decisions based upon overall scientific merit and the overall contribution to the goals of the PSI:Biology and the mission of NIGMS, with the advice and consent of the National Advisory General Medical Sciences Council.
Q. In addition to scientific merit and the availability of funds, the award criteria in the RFA include programmatic priorities. What does this mean?
A. It means that NIH staff will consider overall program goals in making funding decisions. For the high-throughput centers, foremost among the program goals is collaboration with the biology partnerships. For the membrane centers, a crucial goal is the methodology and technology development for structure determination of challenging membrane proteins for which the applicants have offered compelling justification. Another factor in funding decisions might relate to regional distribution in order to take advantage of the resources and scientific talents found across the nation. Scientific and personnel overlaps will be examined carefully. No more than one award will be made to the same principal investigator and other major investigators.
Target Selection
Q. How will the HT-centers select their targets?
A. The first and third target selection goals (structural coverage of sequenced genes and consideration of targets proposed by the scientific community) are PSI Network activities. Each center must identify groups of proteins that the center will work on in meeting these goals. Under terms of the cooperative agreement, all PSI:Biology centers will work with NIH staff to select targets to meet these goals and to determine each center’s tasks. The second goal (structural genomics research project with a significant biomedical theme) is an individual activity for the large-scale centers. Each center will select targets that will lead to unique, non-redundant protein structures that addresses the center’s chosen scientific problem.
Q. Given that 70 percent of the HT-Center efforts will be with unknown collaborators on targets to be determined by the collaborators, do you expect them to still produce 200 structures per year?
A. The citation of 200 structures per year in the RFA is only intended to give a rough indication of the scale of activity that is anticipated. Clearly the number of structures solved will decrease as the complexity of the targets increases. The metric of success for PSI:Biology will be the impact of the solved structures, not the numbers alone.
Q. When an HT-center adopts a target, does it work only on that exact target (meaning a protein of a single specific sequence and function from a given organism)?
A. No. HT-centers will expand around the target to consider homologous proteins from different organisms and orthologues of different function but in the same protein family.
Q. With respect to sequence coverage, will there be centralized coordination of target selection?
A. Yes. The PSI:Biology Steering Committee will coordinate target selection in much the same way as the Bioinformatics Group (BIG) has functioned during PSI-2.
Q. Within the 70 percent effort devoted to partnerships and community nominated targets, what is an acceptable breakdown of effort between these two activities?
A. It is probably not possible to predict this accurately in advance. This will depend on the demand which is to be determined.
Q. How will the membrane centers select their targets?
A. The target selection by the center should reflect a balance between structural coverage of sequenced genes and the elucidation of biomedically important systems and pathways.
Q. Can targets for membrane centers be based on their own biomedical theme?
A. Yes. Up to 70 percent of effort in the membrane centers is expected to be applied to targets that are defined by the investigators in the center.
Q. How many protein targets would be appropriate for membrane protein centers to propose?
A. This is for the applicant to judge based on their experience. You should propose a reasonable number of the time and effort that the budget will support.
Q. Are the membrane protein centers also expected to work on community nominated targets and how will these targets be assigned?
A. Yes. Membrane protein centers are expected to adopt community nominated targets and apply due diligence subject to available budget and feasibility of the problem. Targets will be selected by the center with greatest interest in the biological problem.
Q. For the Partnership applicants, what defines a target and how many targets should be proposed?
A. A target would be defined as a single specific protein in a given organism and its family members within approximately 30 percent sequence identity (i.e., current homology modeling distance). How many targets to propose will depend on the biological problem to be answered. The maximum number is limited by the budget available for structure determinations.
Q. How different do the proposed targets need to be?
A. Structural novelty is one of the criteria for prioritizing targets, but is not the only one. Reviewers will be asked to balance structural novelty with the value of the structures in solving a biological problem. Ideally each structure solved will contribute to both structural coverage of sequence space and the proposed biological problem. However, it is not necessary that all targets fit this framework.
Community Nominated Targets
Q. How can individual R01 funded investigators access PSI resources participate in PSI:Biology?
A. Anyone can nominate a protein to be a target for the structure centers through a link on the PSI Knowledgebase. See: http://cnt.psi-structuralgenomics.org/CNT/targetlogin.jsp.
This option is already in place and will be continued during PSI:Biology.
Q. For a single investigator interested in collaborating with a membrane protein center, what is a reasonable number of targets to suggest?
A. This depends on the biological problem you are trying to solve. But, one specific protein and its family members may be a reasonable starting point.
Facilities, Resources and Environment
Q. Should U54 centers request funding for synchrotron beam time or be members of beam line access groups or is it expected that general user time at beamlines will be sufficient?
A. NIGMS does not have a position on this. Beam time costs are an allowable expense; however, if sufficient time is available through other mechanisms of support, we would rather not pay for it twice.
Q. Can equipment be purchased for use by the centers?
A. Yes. Equipment, including major equipment can be supported as part of center budgets. The cost should be well justified and the proportional center specific usage. It may be useful to spread large acquisition costs over multiple years.
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Questions specific to RFA-GM-10-007 Consortia for High-Throughput-Enabled Biology Partnerships (U01)
Background Information
Q. What is a U01?
A. A U01 is a cooperative agreement research project. It is like a regular R01 research grant in that it describes a single integrated project. It differs in that NIH staff will work more closely with the investigators to help them utilize resources of the PSI:Biology network.
Q. Who are the “Partners” in this RFA?
A. The partners are the RFA applicants. They work with the PSI:Biology network as a whole to form a partnership. The term does not refer to the internal collaborations or partnerships among the investigators associated with a single application in response to the RFA. The partnership applicants may be single investigators, multiple investigators or large networks of investigators such as those supported by the NIGMS glue grant mechanism.
Q. Who or what are the “Consortia” in this RFA?
A. Consortia refers to the formal budgetary relationship between the RFA applicants or “partners” and the PSI:Biology structure determination centers. Once funding decisions to establish the PSI:Biology network have been made, awardees for this RFA will establish consortium financial arrangements with one or more institutions that have received funding through RFA-GM-10-005 and/or RFA-GM-10-006 to establish structure determination centers. These consortium arrangements will enable the structure centers to carry out work on the targets proposed by the partners. The term does not refer to internal consortium arrangements that may also be necessary among the investigators and institutions associated with a single application in response to the RFA.
Q. Does the PSI:Biology initiative take into account post-translational modifications?
A. Yes. This is a great example of where partnerships between those involved with proteomics efforts and those involved with structural genomics could work together.
Q. Is the PSI:Biology initiative limited to protein structures?
A. No. You may apply to work on any cellular components that are amenable to structure determination, including nucleic acids and nucleic acid-protein complexes and molecular assemblies.
Q. Is the work that centers could conduct limited to atomic resolution structure determination?
A. No. The centers may be able to provide other types of biochemical and structural characterizations such as x-ray, EM or light scattering measurements.
Q. How can structural biologists in general participate in this initiative?
A. Obviously structural biologists are expected to participate by applying for U54 center awards. Structural biologists may also play a role in the U01 partnership awards. The solution of many biological problems requires a combination of biophysical techniques. The structure determination centers will be focused on solving the 3D structures of proteins at atomic resolution, primarily by x-ray diffraction and NMR spectroscopy. Solving other aspects of the biological problem will be the responsibility of the partners applying for the U01 awards. For example, large complex structures may benefit by the applying high-throughput approaches to solve subunit and domain structures. This work can be carried out by the structure determination centers. Assembly of these pieces into larger assemblies might be the work of the partners.
Q. If the partnership applicants have special experience in the expression of proteins that will benefit the structure determination work, can they do the protein production, rather than the centers?
A. Yes. Various stages of the pipeline from sequence to structure may be carried out by one side or the other of the partnership.
Q. How much iterative structural work to derive detailed mechanistic information beyond a first pass structure of a given protein target is expected?
A. One goal of the PSI remains the solution of novel protein structures. However, additional structures necessary to establish function, such as structures with bound ligands subsequently identified by the partners may be undertaken. But it is not expected that detailed structure/function studies involving many mutants and series of substrate analogs and inhibitors will be undertaken within the PSI:Biology initiative.
Collaboration
Q. What if I already have on-going collaborations with one of the current PSI structure centers?
A. You should include information about all of your current collaborations to help us avoid conflicts of interest during review. In your application, you may also discuss your preliminary results obtained in collaboration with the current PSI structure centers. However, as noted above, your application should take into account the possibility that your partnership application will be funded, but your current collaborating structure center may not. You should be prepared to work with the investigators funded through the other RFAs.
Q. What if I don’t already have on-going collaborations with one of the current PSI structure centers?
A. You do not need to have any on-going contact or collaborations with the current PSI centers to apply.
Q. Does the application have to come from a group of investigators or can a single investigator apply?
A. The key question is whether the application proposes a sufficient number of protein targets to benefit from a high-throughput approach. So, a single investigator, small group or large network of researchers can apply.
Q. I am a biologist and a colleague of mine is a crystallographer. Can we apply to establish a consortium under this RFA?
A. You may apply for this RFA and the application may include your colleague. However, the application should plan for the crystallographic work to be conducted by the PSI:Biology structure centers, not by your colleague. Your colleague may be involved in other aspects of the project.
Q. I am a crystallographer. Can I submit an application along with my current collaborators?
A. Yes, but the application must indicate the interest and willingness of the investigators to work with the PSI:Biology structure determination centers. The structure determination work described in the application would be carried out by the centers, not in your laboratory. Your laboratory and that of your collaborators would be involved in other aspects of the proposed research.
Q. Will work in the biology labs be conducted prior to structure determination efforts?
A. This depends on the problem and the approach that makes the most sense in the context of this program. Work on structures may be ramped up or down during the course of the project or proceed in parallel at a steady level. However, overall the proposals should plan to make significant use of the structure center resources.
Working with the High-Throughput Centers
Q. Will I know what structure centers will be part of the consortia?
A. You will not know in advance which investigators will receive funding to establish PSI:Biology structure determination centers. Your proposal should be constructed in a way that allows for the possibility of working with any group of investigators who have the necessary resources, facilities, and expertise to carry out the structural studies. Decisions about which partners will work with which structure centers will be made as part of funding decisions for the overall PSI:Biology network and through negotiations among members of the network early in the first year of support.
Q. How should I describe the work that will be done by the centers for structure determination?
A. It may not be possible to describe this work in great detail, but you should be able to suggest the general approach that you would expect and how the partners would work with the centers.
Q. How do I estimate the budget for structure determination centers?
A. The RFA gives some very broad guidelines. 1) No more than half the total direct cost budget should be planned for consortium arrangements with the PSI:Biology structure centers. 2) A rough estimate is $10,000 per soluble protein target. This estimate is actually based on the cost per solved protein structure for the current PSI. Many more targets were attempted than are actually solved. Therefore the figure of $10,000 might more likely be applied per family of closely related proteins. For more difficult proteins, the cost is obviously higher, but difficult to know. Estimate the amount of work based on the level of effort that is expected.
Q. Are the partners limited to working with the high-throughput centers?
A. No. Partners may propose work to be conducted by the membrane protein centers or by both types of centers.
Q. Will communication between the U01 partners and the U54 centers be direct or will the Knowledgebase be a clearinghouse for such communication?
A. Communication between the U01 partners and the centers with which they establish consortia will be direct. The Knowledgebase will facilitate communication between all participants in the PSI:Biology initiative and provide an intranet host site for PSI:Biology Network Steering Committee activities.
Q. Will future opportunities exist for initiating new collaborations with centers in subsequent years once the centers are established?
A. Yes. There will be additional announcements in the future that provide ways for new partnerships to be established between researchers and the PSI:Biology structure centers.
Q. What are the expectations that the centers will produce and distribute protein reagents to partners and community members at large?
A. Centers are expected to deposit clones in the PSI-Material Repository. Proteins will be distributed by the centers to others, including their U01 partners as per the negotiated agreement between them that results in consortium funding of the centers by the partners. Distribution of proteins to other groups would be managed by the centers in the same way as other typical collaborations among scientists and are subject to availability of materials.
Grants Management and Budget Planning Questions
Q. How will the awards to the centers and the partnerships be coordinated?
A. Center awards will be made based on the requested center budget, peer review recommendations, and NIH staff recommendations. Partnership awards will initially be made for the work to be conducted by the applicant research groups, only, and not including funds that are to be used in support of structure determination work at the centers. During the first few months of the award, the partners and centers will negotiate through the PSI:Biology Network Steering Committee to assign specific protein targets to specific centers. The funds to support the effort of the centers on those targets will then be awarded to the partners who will in turn establish consortium agreements with the centers for the work to be done.
Q. Will each partnership awardee work with a single center?
A. Not necessarily. Partners may establish consortium agreements with each of several centers and transfer funds to each appropriate to the work that is to be done. For example, a partnership may be awarded $500,000 in YR1 to support structure determination efforts by the PSI:Biology network. $100,000 might go to center #1, $200,000 to center #2, and $300,000 to center #3 in YR1.
Q. Do you have an estimate of the cost for work to be done on eukaryotic membrane protein targets?
A. No. The best way to get at this may be to estimate how much time and effort is to be devoted to the project by a collaborating center.
Q. Will the amount of money awarded to the partners and centers remain the same for the entire project period?
A. Not necessarily. The partnership awardee has responsibility for monitoring progress of the consortium research and adjusting the level of support appropriately. If progress is inadequate, funds may be shifted to another center. The amount to be provided to each center and to the partners for consortium support of overall center activities will be negotiated annually.
Q. Will the partners pay the centers per structure solved?
A. No. The partners will support the effort of the centers to attempt to solve structures. Therefore, the negotiation should be for the amount of effort and the cost of that effort recognizing that some targets will be fairly easy and others extremely difficult.
Q. Will the partners pay the centers in advance or after the work is done?
A. The partners will pay the centers in advance for the negotiated level of effort to be applied during the budget year.
Q. How will the centers manage the potential year to year fluctuation in support?
A. The U54 center awards are intended to cover about 80 percent of the total center operations and should be sufficient to support key personnel such as group leaders, co-investigators and senior technical personnel. Funds from the partners are intended to cover costs for modest numbers of additional technical staff, supplies and additional facilities costs beyond the center core support. Normal turnover of personnel is expected to leave sufficient flexibility to allow for fluctuations in total effort.
Q. Will funds that are awarded to partners for work by the centers be available for rebudgeting to other purposes?
A. No. These funds will be restricted for support of the negotiated consortium agreements and may not be rebudgeted for other purposes without prior NIH approval.
Q. How should partnership applications handle indirect costs that will be charged by the centers?
A. The RFA instructs partnership applicants to request a 50 percent indirect cost rate on the work that will be done by the centers. The amounts awarded will be negotiated by NIH staff taking into account the actual indirect costs of the centers with which the partners are working in a given budget year.
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