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R E SEAR C H P R O P O SA L SUMMARY & L AY S U M M A R Y S EPTEMBER 1 1 , 2 0 1 2 GSS M. Sadar+ H. Cote 1 EXAMPLES CIHR SCHOLARSHIP OPERATING GRANT 2 RESEARCH PROPOSAL SUMMARY Description (structured summary) • Title and summary that should be written with the supervisor • specific hypothesis of the research • describe the candidate's role on the project • written in general scientific language • Maximum 1 page including references • references can be written in a smaller font, but must be legible 3 SUMMARY PAGE BACKGROUND/INTRODUCTION • Want to capture the attention and interest of the reviewer • Introduce the disease/health problem/field • Provide a compelling rationale for why the research needs to be done – How many people affected? – What is the cost to society/health care system? – What is known/not known 4 SUMMARY PAGE Background or Introduction • End the section with a statement about WHY and HOW you are undertaking the proposed research, or a particular experiment Examples: "To identify molecular regulators of axonal guidance, we will... " or "To establish what family members think about genetic testing, we will... " 5 SUMMARY PAGE Hypothesis • CIHR (as most other agencies) funds hypothesisbased research • Provide a clear statement of your hypothesis Examples: “We hypothesize that [ ] will [ ].” • Then follow with … "To test this hypothesis, we have [three] Specific Aims (or objectives): ... ” [then state these aims] 6 SUMMARY PAGE Aims/Objectives • Bulleted sentences or paragraphs that summarize your specific aims (or objectives). WHAT you intend to do • Emphasize (bold) each aim/objective Examples: “Specific Aim 1 will determine…” or ”Objective 1: To determine...” 7 SUMMARY PAGE Aims/Objectives • Present clear and specific aims that will test your hypothesis • Aims must be feasible within your lab and your proposed project timeline • Aims have to be big enough to stand alone (not just a few experiments) 8 SUMMARY PAGE Methodology or Research Plan • Brief summary of the methodology or HOW you will do this • Explain WHY you are using a specific strategy if it is not obvious • If needed, explain the statistical analysis plan Example: "Our approach will be to identify homologues of XXX domain proteins expressed in the developing brain using [xxx method]...” “ 9 SUMMARY PAGE Significance • Concluding statement(s) that highlights the significance and novelty of the work, including immediate and tangible impact on health of Canadians • Link back to disease if possible • Want reviewer to think: YES!, this work should be done Example: "This work will enhance the understanding of the biology of... and to provide a foundation for elucidating [disease].” “ This research will identify new treatment targets for [disease] and provide …toward new drug development”. 10 SUMMARY PAGE General comments • Write for scientist non-expert in your field of research • Avoid jargon and define abbreviations • Keep the topic focused, a story that makes sense (don’t necessarily need to describe EVERYTHING you plan to do) • Write, then shorten • Even though tight in space, keep “airy” • Check spelling, grammar and punctuation • Avoid references unless really necessary 11 SUMMARY PAGE Main points to address • • • • • • What is the problem? Why it is important to do this research? What you want to do? How you will do it? What the data will tell us? For scholarship: what will your role be? “I will contribute to the experimental design, be responsible for […], will present results at […] and write the manuscript derived from this work.” 12 EXAMPLE Characterization of EPI-001 for the treatment of prostate cancer (Dr. Marianne Sadar, BC Cancer Agency) Background: When prostate cancer progresses to the castration resistant stage, the average survival time is two years. Treatment options currently available for patients with castration resistant prostate cancer (CRPC, also called hormone refractory or androgen independent) provide incremental increases in survival (approximately 2 months). One mechanism suggested to play a role in CRPC is activation of the androgen receptor (AR) in the absence of testicular androgens. Expression of many of the same genes that are increased by androgens become re-expressed in CRPC xenografts. This suggests transactivation of the AR in spite of reduced levels of androgen which is consistent with nuclear localization of AR protein in secondary prostate cancer tumors. Other data supporting the role of AR in CRCP include amplification of the AR gene, delayed onset of CRPC by altering the timing and sequence of use of antiandrogens targeting the ligand-binding domain (LBD), the necessity of AR for the proliferation and tumor growth of castration-recurrent prostate cancer cells, and the fact that the AR can be activated in the absence of androgen (and serum) by alternative signaling pathways involving its N-terminal domain (NTD). The AR NTD contains the activation function-1 (AF-1) region that is necessary for transcriptional activity to the AR, rather than AF-2 in the C-terminal ligand-binding domain (LBD), making the AR unique from other steroid receptors. Recent discovery of constitutively active splice variants of the AR that lack the LBD emphasize that current therapies that target the LBD will not impact the growth of CRPC that express these variants. Thus inhibitors to other domains of the AR are essential. The AR DBD shares high homology with other essential steroid hormone receptors such as the glucocorticoid, mineralocorticoid, and progesterone receptors thereby making this a poor domain for drug development. The AR NTD is intrinsically disordered and thought to require protein-protein interactions for induced folding to acquire transcriptional activity. We identified EPI-001 as a first in class inhibitor to the AR NTD. The mechanism of action involves EPI-001 inhibition of essential protein-protein interactions with the NTD that are required for transcriptional activity. Here we propose to examine known mechanisms of resistant for current antiandrogens and androgen ablation therapies. The hypotheses to be tested are that EPI-001 designed to target the AR NTD will inhibit the activity of gain-of-function mutations in the AR LBD induced by antiandrogens, EPI-001 will show improved response in combination therapy, and resistance to EPI-001 will not occur by a mechanism of mutations in the AR NTD. These hypotheses will be tested in 4 Specific Aims. Specific Aims - Aim 1 will determine if resistance to EPI-001 will develop with long-term exposure. Aim 2 will examine if EPI-001 inhibits the activity of clinically relevant AR mutations originally identified in patients with resistance to antiandrogens. Aim 3 will investigate if resistance to EPI-001 will develop in vivo. Aim 4 will test EPI-001 in combination therapies with antiandrogens or docetaxel. Significance - There are no long-term effective therapies for CRPC. We have identified the first inhibitor to the AR NTD which has attracted high enthusiasm in the scientific and medical communities because of its potential as a therapy for lethal CRPC. The studies proposed here will yield insight into the clinical application of EPI-001 and focuses on identifying its potential niche in the clinic (i.e., chemotherapy resistant, antiandrogen resistant patient populations) and testing the possibility for resistance to develop. 13 EXAMPLE Mitochondrial DNA damage in infants exposed to HIV antiretroviral drugs in-utero (Helene Cote) Background: Exposure to antiretroviral nucleoside analogues in utero and neonatally has been associated with high serum lactate levels, and mitochondrial DNA (mtDNA) depletion in infants born to HIV-infected (HIV+) mothers. This effect appears mostly reversible upon interruption of drug exposure. Preliminary data collected as part of our ongoing studies of mitochondrial toxicity (mtDNA depletion) in infants born to HIV+ mothers suggest that exposure to antiretroviral drugs, especially at conception or very early in embryonic development may be associated with significant mtDNA damage (mtDNA mutations/deletions). The mitochondrial polymerase repair mechanism is relatively poor and mtDNA mutations, including those nucleoside-induced, accumulate in the heteroplasmic genome over time. Congenital and acquired mtDNA mutations have been implicated in numerous diseases and conditions, often associated with aging. Antiretroviral-induced mtDNA damage in the embryo may have unforeseen long-term effects for the infants and their future offspring. We have an opportunity to evaluate mtDNA quality from two ongoing multicenter observational cohorts of infants born to HIV+ mothers who were treated with antiretroviral drugs during their pregnancy. Objectives: To determine whether exposure to antiretroviral drugs early in embryogenesis causes detectable mtDNA damage, which may have longterm unknown health consequences in the HIV uninfected antiretroviral-exposed population. Hypothesis: Infants born to HIV+ mothers who received HAART during pregnancy will have significantly more mtDNA damage/mutations than infants born to HIV-uninfected mothers and more so if drug exposure was at the time of conception as opposed to the 2nd or 3rd trimester of the pregnancy. Research Plan: Study subjects will be infants born to HIV-infected mothers at three Ontario and B.C. hospitals and enrolled in two ongoing observational mitochondrial toxicity studies. A blood sample is collected from the infant at the time of PKU testing, along with a blood sample from the mother. Demographic data, treatment history, and other relevant information is also collected. DNA will be extracted from the blood and subjected to longtemplate PCR to amplify the whole mtDNA genome. The mtDNA consensus sequence will be compared between infants of two groups: exposed to antiretrovirals in utero (N=70), and unexposed controls (N=42). Within the exposed group, exposure to HIV drugs at time of conception (N=20) will also be compared to exposure only in 2nd or 3rd trimester of pregnancy (N=50). To compare the degree of heteroplasmy (mutations) present in the mtDNA between these same groups, two regions (D-loop and ATPase 6) will be amplified by PCR and cloned from each infant and their mothers (N=50 for exposed and 20 controls), and 96 sequences will be determined per subject. As mtDNA is maternally inherited, infant and mother mtDNA sequences will also be analyzed for differences between them. Sampling size permitting, the effect of different antiretroviral drugs on mtDNA will also be investigated. Significance: While the benefits of treating HIV+ pregnant women for the prevention of mother-to-child transmission of the HIV virus are undeniable, the molecular effect of drug exposure during embryogenesis on mtDNA has not been studied in humans. Global treatment targets of “3 million by 2005 (3 by 5) will include treatment -with nucleoside-containing regimens- of young HIV+ women living in resource-poor settings, with limited reproductive choices. It is imperative to understand as best we can the consequences on the mtDNA genome of conceiving while on HIV antiretroviral therapy. This research will not only improve our understanding of the drug toxicity mechanisms, it may influence the timing and composition of antiretroviral therapy received by HIV+ women of child-bearing age. 14 L AY SUMMARY CIHR Scholarship language: • Describe your project in a way that is accessible to a lay audience • Be sure to indicate how your proposed research can improve personal health, the health of populations and/or the health delivery system • This information is used by CIHR to inform the public and Parliament about the valuable research supported through public funds • Maximum of 2000 characters = this text x 6 15 L AY SUMMARY • What makes your work interesting and worth doing? • How will your findings make a difference in the health of Canadians? • Typically the first thing the reviewer reads → first impression 16 LAY ABSTRACT Definition, purpose • Not a ‘dumbed down’ version or research summary, nor a cut and paste of it • A clear, plain explanation of the research that anyone should understand • Must communicate to a wide audience – Non-expert reviewers – Patients/advocates – Press releases – Attracting donors – Fund raising and government lobbying 17 LAY ABSTRACT Definition, purpose • Lay abstracts provide the context for the research • Purpose of the research, its background and significance. • Less important to explain methodology in detail • Describe the “big picture” and the gains 18 LAY ABSTRACT The challenge • Balance between over-simplification and explaining the details of cutting-edge research • Balance between accuracy and information overload • Using lay language (your 15 year old niece or grandmother should understand) 19 PROPRIETARY/CONFIDENTIAL INFORMATION • No proprietary confidential information! GSS M. Sadar 20 LAY ABSTRACT Title • Short and simple • Grasps the main point • Enticing • Does not need to be the same as your research proposal 21 LAY ABSTRACT 1st Sentence • Crucial • Need to engage the reader and invite them to read on • Try to explain your research in 25 words and then use this as your first sentence 22 LAY ABSTRACT How Lay is Lay Enough? • Have a friend or a family member point out the phrases and concepts that they don’t understand. • Ensure that the average person can relate to the problem 23 EXAMPLE 24 EXAMPLE Cellular aging in HIV-infected people We all accumulate mutations within our mitochondrial DNA (mtDNA) which encodes proteins necessary for our energy production. The more mutations we accumulate, the less we can produce energy, the less we can maintain the health of our tissues. This mitochondrial aging is believed to be one of the main reasons behind aging and age-related diseases. mtDNA mutations can be inherited or caused by inflammation and oxidative stress. However, certain drugs such as the ones used to treat HIV are believed to also induce mtDNA mutations. Evidence is accumulating that HIV-infected people age faster than non-infected people. They have diseases normally seen in older people earlier in life. It is unclear whether this is because of their HIV virus (which can cause chronic inflammation) or because of the side effects of the antiretroviral drugs they take to treat their disease. It is technically challenging to study mtDNA mutations because there are hundreds of copies of mtDNA in each cell. We have developed a deep sequencing-based methodology to detect low frequency mtDNA mutations and distinguish them from background PCR and sequencing errors. We will use a cell culture model to determine whether commonly used HIV drugs can indeed induce mtDNA mutations. We will also test samples collected from HIV+ and HIV- individuals, young and old, treated with antiretroviral or not, as well as umbilical cord progenitor cells from infants born to HIV+ or HIVmothers, to investigate the relationship between mitochondrial aging, age, HIV infection and exposure to HIV therapy. It is important to figure out what may accelerate aging in HIV+ individuals: the virus or the medications? 25 GENERAL WRITING TIPS • Shorter common words (e.g., use instead of utilize) • Avoid complex logical arguments – be brief • Short sentences (15-20 words) • Write, then shorten • Use analogies and relate science to everyday life • Explain what key scientific terms mean • Grade 10 level language • Follow formatting guidelines 26