Writing Specific Aims and Narrative Part 2

Do NOT write Aims with non-specific and vague unsupported statements: To study the effects of… To explore the reasons for… To better understand the effects of… To investigate the causes of… To research why… Aims use SPECIFIC language: Specific Aim 1. Measure levels of calcium and magnesium in the wound microenvironment over 21 days in an established rodent wound healing model. Male Wistar EK-21 rats with incisional dorsum skin wounds will be blindly scored daily for evidence of hemorrhage, ulceration, fibroblast contraction, and scab formation using standardized assays. Wound extracellular Ca++ and Mg++ and pH in wounds will be measured daily and matched to the patterns of wound changes over 21 days.  What are my expected outcomes?  What is the probability my study will be successful and exert a powerful sustained influence on the field(s) specifically and more generally—impact  The NIH Payoff paragraph—why should they fund this work?  Perhaps you are developing a new treatment, vaccine, disease model, or diagnostic tool  Expected outcomes must be specific and credible—it’s the return on investment for NIH  Do not write in the future tense—“this is what we believe that we will have accomplished…” but direct present tense— “We expect to determine…”  Impact — How will these stated outcomes fill the identified need and thereby advance research (and the mission of the agency, if possible)? Expected Outcomes: By the end of our study, we expect to more fully characterize the wound microenvironmental changes in pH; Ca and Mg levels; and changes in microvasculature, providing an in-depth insights into wounds as they heal. Innovation: This will the first study using an established wound model to correlate wound healing parameters to specific wound microenvironmental changes in pH, Ca++ and Mg++, and alterations in microvasculature using novel highthroughput assays. Impact/Payoff: Insights into the mechanisms of wound healing will provide knowledge for the wider scientific community and clinicians to identify specific therapeutic targets and strategies to more effectively managing wounds. In specific aims page, significance, and approach use specific language such as: Our proposal addresses the 3 objectives of NCI RFA-CA-15-008… Our specific aims address two objectives of the National Institute of General Medical Sciences (NIGMS), namely… This research is in direct response to the NIH 2016-2020 Strategic Initiative for Brain Research through Advancing Innovative Neurotechnologies (BRAIN) that addresses “nextgen invasive devices to record and modulate the central nervous system of patients with spinal damage. The Problem Knowledge Gap/Critical Need Proposed Solution/Hypothesis Specific Aims Expected Outcomes and Impact Long-term Goals  The Problem Colon cancer is a fatal disease if not detected early. Current medical practice in the US is screening colonoscopies for all over age 50, but colonoscopies are expensive and invasive. Screening for occult blood in stool is inexpensive but ineffective, and many cancers are missed. A blood test that could accurately detect colon cancer very early would save lives.  Gaps in Knowledge Current approaches for measuring proteins in blood are relatively insensitive, and unlikely to detect cancers early enough. Human variability and low signal means many independent patient samples must be measured.  The Solution New proteomic technologies developed by my group offer both the sensitivity and throughput needed to identify and validate blood biomarkers for early detection of colon cancer.  Long-term Goal Using bioinformatic methodologies, we will develop key biomarkers for other cancer types (e.g., lung, pancreatic, brain) for high-throughput proteonmics  Hypothesis We hypothesize that colon cancers can be more effectively detected using sensitive blood biomarkers.  Action Plan Specific Aim 1: To identify plasma proteins associated with early stages of colon cancer using novel mass spectrometric approaches that provide absolute protein abundance measurements down to pg/ml levels. These measurements will be applied to a unique cohort of colon cancer patients available from clinical collaborators Specific Aim 2: To carry out a novel bioinformatic analysis of over-represented proteins for enrichment of specific functions using a variety of innovative software tools including KEGG, BIND, and MetaCor Specific Aim 3: To select and validate candidate biomarkers Candidate biomarkers selected on the basis of functions known to be associated with carcinogenesis will be verified by orthogonal approaches. The top ten ten verified candidates will be assessed in 1000 prospectively collected plasma samples from early stage colon cancer patients, using a novel high throughput proteomics approach  Expected Outcomes and Impact The end product of this research will be an affordable accurate blood test for early detection of colon cancer without colonoscopy. Our approach will use many previously successful methods (preliminary studies) to increase the probably of success in this proposal. Successful demonstration of this approach in colon cancer will enable application to other cancers in need of early detection biomarkers. Future directions of this research also include the application of a systems biology approach to the large datasets generated in the discovery phase that will provide new insights about the earliest stages of colon cancer. Developing such a novel treatment program for CRC directly addresses one NCI Provocative Questions and is a central mission of the NIDDK, namely…  Lack of original or innovative ideas  Unrealistic or unfocused   Are the aims specific and focused?  If there are risks, justify why it’s important to pursue and how knowledge would move the field if the aim was not met Poorly justified   Relationship of aims to what’s known and what’s unknown should be obvious Purely descriptive, not hypothesis-driven  “This proposal looks more like a collection of experiments in which the applicants are simply listing experiments according to their expertise in specific techniques instead of testing an underlying hypothesis”  “Our enthusiasm was dampened by lack of a hypothesis driven by a specific mechanism”   Lack of cohesiveness  Must be thematically related and form a cohesive unit  Think of a central hypothesis unifying aims Interdependence of aims    Describing techniques    Avoid interdependent aims unless there is no doubt that the early goal will be achieved Avoid “look and see” structure of an aim Do not provide details of methods in Aims Overly ambitious  2-4 Aims (R01), 1-2 Aims (R03,R21)  Gives impression proposal is unfocused or you have not thought the proposal through No significant impact on the field even if aims achieved Review Problem % Goals overstated, overly ambitious, unrealistic 45 Poorly focused, inadequately conceptualized 38 Hypotheses not clearly articulated 50 Inouye S. Evidence-based guide to writing grant proposals for clinical research. Ann Int. Med 142:274, 2005 1. Project Summary    Project Summary — succinct and accurate description of the proposed work Informative to other persons working in the same/related field and for scientifically/technically literate reader ≤30 lines of text 2. Project Narrative    This is the second component of the “abstract” that defines the “relevance” Using no more than 2-3 sentences, describe the relevance of this research to public health Use plain language understood by the general public (Congress)  Write AFTER the Aims Page  Often the first thing read by reviewers and by congress  Potential funders will read to determine if the project fits with the agency’s mission and support   Project potential to improve public health must be clearly articulated Your project will not be of interest unless it grabs their attention—and often it written too technically  How to describe the relevance to human health in lay language?  Start with what disease state or problem you’re tackling  What you plan to do to overcome the problem  How this will help diagnose/treat people with the disease  Ultimately, FOCUS on how is your work relevant to public health Legionella pneumophila uses a specialized type IV secretion apparatus, also known as the Dot/Icm system, to secrete over 150 effector proteins directly into the host cell. The translocated bacterial effectors establish a vacuolar niche that supports replication of L. pneumophila in eukaryotic cells. While there is an extensive literature describing how several of these effectors alter host cell functions, the targets of most have remained elusive…. Legionnaires’ disease is a rapidly progressive, deadly disease caused by the bacteria Legionella pneumophila, which replicates in cells of infected individuals (host). To replicate itself inside the host cell, bacteria injects ~150 proteins. Our research will use a large-scale approach to identify the targets of these injected bacterial proteins, thereby identifying the host cell proteins that are destabilized by the injected bacterial proteins. Once we identify which bacterial proteins are manipulating which host proteins, we can disrupt these interactions, halting the disease. This study will lead to new highly effective classes of antibiotics to treat bacterial infection responsible for Legionnaires’ disease.