Beruflich Dokumente
Kultur Dokumente
Translational research: translates basic science discoveries into clinical applications, and/or uses clinical observations to generate new research topics. Focus is on the integration of activities from bench to bedside. Translational research is increasingly a focus of funding agencies Makes it possible to expand your funding base Makes you eligible for new types of federal and, especially private, grants Often involves new collaborations with clinical colleagues Can involve prospective clinical trials, or extensive use of patient samples or information
Translational Projects
Identify a translational opportunity - this can be a project that involves clinical specimens Identify a clinical colleague with whom to work This can be on-site or off-site On-site is better for grantsmanship purposes - easier to integrate. Needs to be a two-way street Better if the basic research plays some role in selecting patient samples to be used - what types of clinical specimens? Are specimens analyzed in some way so as to rule them in or out of the study? How does your research feed back into clinical practice and the understanding of disease?
Basic Grantsmanship
PI and a Co-PI - a joint R01 Both individuals need to benefit and play an active role Take IRB issues seriously - NIH spells out specific pieces of information that you must include regarding patient enrollment Seek advice from senior colleagues Prepare your grant sufficiently in advance so that you can show it to colleagues - no excuse for not doing this!
K23 - Mentored Patient-Oriented Research Patient The purpose of the Mentored Patient-oriented Research Career Development Award (K23) is to support the career development of investigators who have made a commitment to focus their research endeavors on patient-oriented research. This mechanism provides support for three to five years of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators focusing on patient-oriented research. Clinically trained professionals or individuals with a clinical degree who are interested in further career development in biomedical research that is not patient-oriented, should apply for a Mentored Clinical Scientist Career Development (K08) Award
Specific Aims
One page maximum Should be self explanatory - tells a story, not just bare bones specific aims 3-5 Specific Aims Straight forwards Aims with best prelim data go first, put risky aims at the end Aims should talk to and build on one another
D1. Explore the role of the bridging sheet region in receptor binding and virus infection. Does this region represent a conserved coreceptor binding site, does it govern coreceptor binding affinity, and is it involved in triggering the fusion-inducing conformational changes? D2. Examine the relationships between Env-coreceptor affinity and virus tropism, pathogenesis, and receptor density. We have developed technologies needed to rigorously measure Env-coreceptor binding constants, and can now study the relationship between this and viral tropism and pathogenicity using a panel of well characterized primary HIV, SIV, and SHIV Env proteins. D3. Determine how many receptor binding events are needed to activate HIV and SIV Env trimers, and explore the consequences this has for synergistic neutralization of HIV by different classes of entry inhibitors. Our preliminary studies indicate that multiple receptor binding events are needed, which in turn led us to hypothesize and subsequently demonstrate that HIV can be synergistically inhibited by different classes of entry inhibitors.
Preliminary Results
5-10 pages, in my opinion A critical section - B/S should convince reviewers that you are proposing something that is worth doing, Prelim Results should convince them that you can actually do it Refer to Spec Aims, noting how specific preliminary findings will make it possible to achieve your goals Identify key technologies, reagents and collaborations; can list in Section C1 (reagents/assays)
Experimental Design
Many ways to do this; different reviewers look for different things If you are a younger investigator, place more emphasis on how you will do things, have sections in possible outcomes and pitfalls Dont build a house of cards - i.e. entire project, or much of it, rests on a reagent that does not presently exist Refer back to Prelim Results
D1a. Selection of mutations and choice of Env. Initially, we will introduce 13 single amino acid substitutions in the bridging sheet region of IIIB. As shown in Section C3, we have already gotten a good start on this project, and the specific mutations are listed in Table 1. A potential problem with our approach is that the HxB gp120 binds to CXCR4 with poor affinity . By contrast, HxB-V3-BaL gp120 binds well to CCR5. Thus, while it is relatively trivial to study the impact of these mutations on CXCR4-dependent membrane fusion activity, either in the context of cell-cell fusion or virus entry assays, it is more difficult to measure their impact on gp120-CXCR4 binding. As discussed below, we should be able to accomplish this goal. However, it may prove desirable to place some of these mutations into an X4 Env protein that binds to CXCR4 with high affinity, though we have not yet identified such a protein, at least for HIV-1. This is discussed in Section D1d.
Money
- Start-up Start- Grants
The Science
- Focus; getting papers out - Resources at Penn - Collaborations, affinity groups
Technicians
There is a great pool of technicians in the Philadelphia area - lots of excellent colleges and universities Many students want to work for 1-3 years before going to grad school or med school, and so have a reason to do well Get to know your personnel person; know the rules; give your technician feedback, both positive and negative If someone is not working out, you have to cut them lose; pay attention to the probationary period