The most important part of a medical research application is the Specific Aims page. The reviewers have to understand, appreciate, and be convinced of your idea by the time they finish reading this one page. It is where you provide the summary of your entire project in persuasive terms that convince the reviewer that you are the right choice to advance the science in your field. On this single page you will immediately establish the problem, both in terms of health and science, and demonstrate how you will bridge the gap of what is missing in the field. The following are the key questions that must be answered on this page:
1. What is the goal of your project?
This will be stated in your introductory paragraph. The goal will address the gap that your research will undertake to fill. You will also address the importance of your research via the “so what question”.
The development of the mammalian immune system is typically thought to occur in a linear fashion, from immaturity to maturity as a function of antigen exposure. Previous findings in birds and in mice, however, indicate that this view is oversimplified. Thus, in these species, the developing immune system appears to be “layered” in a manner that is independent of antigen exposure, beginning as a multilineage fetal system that is replaced by an anatomically and biologically distinct multilineage system after birth. If so, then developmentally ordered and unique hematopoietic stem/progenitor cells (HSPC) could give rise to distinct lymphocyte lineages at different stages of development.
2. What data or advances are you bringing to the table?
Your preliminary data will set the stage for your credibility, which helps convince reviewers that you are able to undertake this proposal. The more preliminary results of previous findings you have, the more convincing your case will be.
In ongoing experiments, we have found that such immune system “layering” occurs in humans. Our preliminary data show that: (1) the human fetus can mount a vigorous immune response to exogenous antigens;4 (2) the human fetal immune response to exogenous antigens can be actively suppressed by antigen-specific Tregs;4,5 (3) fetal Tregs are derived from a fetal-specific lineage of T cells; (4) fetal and adult HSPCs give rise to distinct populations of T cells; and (5) fetal HSPC-derived T cells show an enhanced ability to generate
Tregs during thymic maturation and upon exposure to foreign antigens in vitro.6 These data suggest that the human immune system is comprised of two distinct waves: one generated from a “fetal” HSPC that exists in utero in the fetal liver and bone marrow, and another generated from a superseding “adult” HSPC that resides in the bone marrow at later time points. The former gives rise to an immune system that is prone to deliver a tolerogenic response to foregin antigens. The latter gives rise to an immune system that is more likely to generate an immunoreactive responses (e.g., one including cytotoxic T cells and neutralizing antibodies).
3. What is your central hypothesis?
Your hypothesis embodies the critical need for your research and is the central part of your proposal. It is the solution that solves the problem. Your hypothesis is the reason for your project and must be specific.
Given these findings, we hypothesize that physiologic layering of immune system ontogeny leads to a normal range in the ratio of fetal- to adult-type T cells at birth, with some neonates exhibiting a higher fraction of fetal T cells than others; and that those with a high ratio of fetal/adult T cells will generate predominant Th2 responses to routine childhood immunizations.
4. What are your specific aims?
Your aims will test the hypothesis and need to be detailed. They should result in something that you can measure. In other words, they are exactly what its name implies – specific. They should also be independent of each other, and should not be overly ambitious. The above hypothesis will be tested via the following specific aims, which are specific and independent of one another:
Specific Aim 1. To determine the normal range of fetal to adult T cells in the umbilical cord blood of the full term neonate.
Specific Aim 2. To determine whether those full-term neonates with a high ratio of fetal/adult T cells are more likely to generate a Th2-polarized immune response to routine childhood immunizations.
5. What will be the ultimate results of your study?
The Specific Aims page will end with the benefits that are expected from your study. It is the outcome section of your proposal and the major reason you received the funding to undertake your study.
We anticipate that this study will reveal normal variation in the ratio of fetal to adult T cells at birth and that such variability in this ratio will be directly related to – and possibly causal of – a Th2 skew that results in a poor response to childhood vaccines and a heightened predisposition to childhood infections and to atopic disorders. If so, these modalities aimed at changing this ratio more towards the adult lineage at birth may provide benefit to a substantial number of newborns.
Your goal, data, hypothesis and specific aims will be the central focal points for your entire proposal. These are the most difficult to write, and you will probably revise them many times before you settle on the final submission. Ultimately, this is the page that will determine the fate of your proposal because it demonstrates how all the pieces will fit together to develop a paradigm shift in the field.
Examples excerpted from:
McCune, Joseph. “Human immune system layering and the neonatal response to vaccines.” National Institute of Allergies and Diseases Sample Grant Application. 14 Jun 2010. Web. 2 Jul 2015.
Full text of the sample proposal by Joseph McCune of The Regents of the University of California, San Francisco, posted online by the National Institute of Allergies and Diseases is available at: http://www.niaid.nih.gov/researchfunding/grant/Documents/McCunefull.pdf
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