2. Why R03? Something is better than nothing The R03 (Small Grant) mechanism supports small research projects that can be carried out in a short period of time with limited resources. Up to two years Direct costs $50,000 per year The R03 cannot be renewed One resubmission (A1) is allowed No preliminary data are required but may be included if available. A doctoral student may not apply for an R03

3. So, you may consider an R03 when you have: 1.A novel, biomedically relevant idea 2.Expertise and facilities to test your idea 3.No (or little) preliminary data You need to present a hypothesis and suggest methods, preferably innovative, to test this hypothesis. You want to test if this new approach is feasible. You may propose to develop a new technology.

4. Pilot or feasibility studies Secondary analysis of existing data Small, self-contained research projects Development of research methodology Development of new research technology NIH-formulated Types of R03 Projects : Unfortunately, not all NIH Institutes accept investigator-initiated R03 proposals.

5. R03 Participating Institutes and Centers (11): NIH Institutes and Centers that accept investigator-initiated R03 applications in response to the Parent R03 Announcement - (PA-11- 262): NHGRI, NIA, NIAAA, NIAID, NIBIB, NICHD, NIDA, NIEHS, NIMH, NINDS, NINRPA-11- 262)NHGRINIANIAAANIAIDNIBIBNICHDNIDANIEHSNIMH NINDSNINR R03 Non-Participating Institutes and Centers (13): NIH Institutes and Centers that DO NOT ACCEPT R03 applications in response to the Parent R03 Announcement but ONLY accept R03 applications in response to their specific funding opportunity announcements: FIC, NCATS, NCCAM, NCI, NEI, NHLBI, NIAMS, NIDCD, NIDCR, NIDDK, NIGMS, NLM, ORIP.FICNCATSNCCAMNCINEINHLBINIAMS NIDCDNIDCRNIDDKNIGMSNLMORIP NIH Institutes and Centers that DO NOT use the R03 mechanism (1): NIMHDNIMHD.

6. How to choose between R03 and R21? R21 is a Exploratory/Developmental Grant  Up to two years  Total direct cost  $275,000  Cannot be renewed  One resubmission (A1) is allowed  No preliminary data are required but may be included  Exploratory, novel studies that break new ground or extend previous discoveries toward new directions  High risk-- high reward studies that may lead to a breakthrough in a particular area, or result in novel techniques, agents, methodologies, models...  Projects should be distinct from those supported through the traditional R01 mechanism.

7. Critique 1 notes that solid preliminary data would be required to demonstrate likelihood of success. Meanwhile, R03 guidelines stress that “Preliminary data are not required.” A strong conceptual framework and an innovative approach to the problem are the criteria of an R03 proposal. From the Introduction of my amended submission: It is stated that “Dr. Tatulian has no direct experience with the synthesis of peptides and with the proposed native ligation strategies…” This is simply not true because we have been among the pioneers of creating segmentally labeled, semi-synthetic proteins and structural analysis by FTIR.

8. From the final summary statement: …the principal investigator… was highly responsive to previous critiques… Overall, the panel members expressed considerable enthusiasm for this outstanding application that is likely to have a high impact on the field of protein toxin translocation. Previous concerns included the lack of preliminary data, the perception that the PI lacked expertise to generate semi-synthetic peptides, the ability to generate T-domain in functional form... These critiques are countered by arguments that preliminary data is not required for the R03 mechanism where the goal is to establish feasibility (or not) and the PI’s documented success in using semi- synthetic synthesis in his previous work.