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Remember the most important rule of grant writing zWrite with a purpose – not to fill 25 pages! zEverything you put into your grant should have a purpose.

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Presentation on theme: "Remember the most important rule of grant writing zWrite with a purpose – not to fill 25 pages! zEverything you put into your grant should have a purpose."— Presentation transcript:

1 Remember the most important rule of grant writing zWrite with a purpose – not to fill 25 pages! zEverything you put into your grant should have a purpose and help to build the argument for funding zWe already talked about the purpose and writing of the Specific Aims, Background & Significance, and Preliminary Data sections zNow you are ready to get into your Experimental Plan

2 Experimental Plan zThis is the place to flesh out your specific aims with real experiments zBasically follow a more detailed version of the specific aim anatomy. zEssentially you write this like a paper, you just don’t have the data yet. zYou still can construct arguments, weigh evidence etc. zDo not provide a boring technical run down of your experiments! zMake sure the rationale for doing an experiment is always clear, remember the ‘Biology First’ rule. Lead with the problem, then provide the solution. zArgument your way through the project guiding the reviewer through the logic and prioritization zConsider to summarize what you will learn at certain key points

3 Experimental Plan zYou have to convince the reviewer that the methods are appropriate, that the experiments have a high likelihood of success and that you are well versed in these approaches zMake sure that your experiments test the hypothesis and that you provide a specific expectation towards the outcome zDiscuss different possible outcomes and make clear how such results would impact your hypothesis and how that will change your plans. zWhat if your approach fails? Provide a discussion of potential pitfalls or problems and offer solutions to these problems or back up strategies zIf your strategy is complicated a figure might help the reviewer to understand it.

4 How to handle technical detail (especially in the experimental plan) ? zBe mindful of the diversity of reviewers zSome will hear about your area for the first time, while others are the world’s expert on the subject zYour writing has to please & convince both camps zDon’t loose the generalist, and let enough technical sparkle shine through to convince the specialist that you know your stuff zHow can you have it all in one document?

5 How to handle technical detail (especially in the experimental plan) ? zOgres have layers! Try to write an onion. zStart the Aim/Subaim with a discussion of the rationale/question zSummarize your technical solution in a way everybody on the panel should understand (e.g. we will test importance by constructing and analyzing mutants) zThen dive into the nuts & bolts (how exactly will you make the mutants) zWrap up with a discussion of what you will have learned that again is conceptual and not technical zThe beginning and end is for everybody the center targets the specialist, make sure that the generalist reviewer can understand beginning and end without the center

6 The Finish line zMake sure you have sufficient time to finish zProposals riddled with typos and grammatical errors come across as sloppy and annoy the reviewer zMake sure your references are complete and correct. zHave a copy editor!

7 Random thoughts on style zObviously different folks write differently zSome simple things: zYou do not “hope” you expect zActive can be more engaging than passive (phenotypes will be analyzed by … We will analyze the phenotypes) zEvery time you want to write “make”, “do”, “look” … think if there might not be a more specific and polished term at your disposal zLet your enthusiasm shine through, find the level of hype you personally are comfortable with zRespond politely and constructively to reviewer criticism zIf they did not understand something, do not point out that they are idiots, apologize for making it not clearer and then do a better job in constructing the argument zYou can not fight the reviewers you have to win them over

8 Some web-resources: zhttp://webs.cb.uga.edu/~Estriepen/biopara/cb8500grants.htmlhttp://webs.cb.uga.edu/~Estriepen/biopara/cb8500grants.html zhttp://www.hfsp.org/how/ArtOfGrants.htmhttp://www.hfsp.org/how/ArtOfGrants.htm zhttp://www.niaid.nih.gov/ncn/grants/default.htm

9 Toxoplasma & apicomplexan host cell invasion

10 The three kingdoms of life (Mitch Sogin’s 16s RNA tree)

11 Alveolata CiliataApicomplexaDinoflagellata

12 Alveolata zCortical alveoli or inner membrane complex (flattened membranous cisternae underlying the plasma membrane zSubpellicular microtubuli zMitochondria with tubular cristae zMolecular phylogeny based on rRNA, tubulin and several other genes solidly supports this grouping MT IMC PM

13 Alveoli (IMC) and apical complex (nice figure by Marc-Jan Gubbels)

14 Apicomplexa zCells contain an apical complex which is an assemblage of cytoskeletal elements and secretory organelles zNo flagella or cilia except for the microgamete (sperm) zAll members of the phylum are parasitic

15 Apicomplexa zApicomplexans are haplonts and meiosis directly follows fertilization zAll replication occurs inside of host cells (with the exception of the conclusion of meiosis in certain species) zThere are several invasive zoite stages

16 Experimental Plan zThis is the place to flesh out your specific aims with real experiments zBasically follow a more detailed version of the specific aim anatomy. zEssentially you write this like a paper, you just don’t have the data yet. zYou still can construct arguments, weigh evidence etc. zDo not provide a boring technical run down of your experiments! z Make sure the rationale for doing an experiment is always clear, remember the ‘Biology First’ rule. Lead with the problem, then provide the solution.

17 Experimental Plan zYou have to convince the reviewer that the methods are appropriate, that the experiments have a high likelihood of success and that you are well versed in these approaches zMake sure that your experiments test the hypothesis and that you provide a specific expectation towards the outcome zDiscuss different possible outcomes and make clear how such results would impact your hypothesis and how that will change your plans. zWhat if your approach fails? Provide a discussion of potential pitfalls or problems and offer solutions to these problems or back up strategies zIf your strategy is complicated a figure might help the reviewer to understand it.

18 How to handle technical detail (especially in the experimental plan) ? zBe mindful of the diversity of reviewers zSome will hear about your area for the first time, while others are the world’s expert on the subject zYour writing has to please & convince both camps zDon’t loose the generalist, and let enough technical sparkle shine through to convince the specialist that you know your stuff zHow can you have it all in one document?

19 How to handle technical detail (especially in the experimental plan) ? zOgres have layers! Try to write an onion. zStart the Aim/Subaim with a discussion of the rationale/question zSummarize your technical solution in a way everybody on the panel should understand (e.g. we will test importance by constructing and analyzing mutants) zThen dive into the nuts & bolts (how exactly will you make the mutants) zWrap up with a discussion of what you will have learned that again is conceptual and not technical zThe beginning and end is for everybody the center targets the specialist, make sure that the generalist reviewer can understand beginning and end without the center

20 The Finish line zMake sure you have sufficient time to finish zProposals riddled with typos and grammatical errors come across as sloppy and annoy the reviewer zMake sure your references are complete and correct. zHave a copy editor!

21 Random thoughts on style zObviously different folks write differently zSome simple things: zYou do not “hope” you expect zActive can be more engaging than passive (phenotypes will be analyzed by … We will analyze the phenotypes) zEvery time you want to write “make”, “do”, “look” … think if there might not be a more specific and polished term at your disposal zLet your enthusiasm shine through, find the level of hype you personally are comfortable with zRespond politely and constructively to reviewer criticism zIf they did not understand something, do not point out that they are idiots, apologize for making it not clearer and then do a better job in constructing the argument zYou can not fight the reviewers you have to win them over

22 Some web-resources: zhttp://webs.cb.uga.edu/~Estriepen/biopara/cb8500grants.htmlhttp://webs.cb.uga.edu/~Estriepen/biopara/cb8500grants.html zhttp://www.hfsp.org/how/ArtOfGrants.htmhttp://www.hfsp.org/how/ArtOfGrants.htm zhttp://www.niaid.nih.gov/ncn/grants/default.htm

23 Apicomplexa are intracellular parasites zAs almost all apicomplexa T. gondii only replicates within cells zGood experimental system for cell biological and genetic approaches

24 Three modes of intracellular development & replication

25 T. gondii and host cell invasion zToxoplasma is an opportunistic pathogen zToxoplasma does not enter the host cell by phagocytosis zInvasion results in the formation of a specialized compartment the parasitophorous vacuole zParasite motility is needed for invasion (the gliding machinery) zProtein secretion from several secretory organelles is involved in invasion and manipulation of the host cell

26 The Toxoplasma life cycle From Chidoni, Moody & Manser, 2001

27 Toxoplasma is an opportunistic pathogen z15-70% of the adult population is chronically infected (current rate in the US is 21.5%) zMost people show no or only benign symptoms (head ache, sore throat, lymphadenitis, fever) zIn rare case ocular involvement zTwo situations can lead to severe disease: loss of a functional immune system and primordial infection during pregnancy

28 Congenital toxoplasmosis is a problem in 1/1000 pregnancies zBoth the probability and severity of the disease depend on when the infection takes place during pregnancy (early: low transmission, but severe disease, late: high transmission, more benign symptoms) zChildren who are asymptomatic at birth often can develop disease later on

29 Treatment is available zTreatment against parasites as well as to alleviate the symptoms are quite successful zDespite calcification throughout the brain this 10 month old child developed completely normal

30 Do you have to get rid of your cat when you are pregnant?

31 T. gondii is a major pathogen in late stages of AIDS z25% of all seropositive AIDS patients develop severe Toxoplasma encephalitis zTE can be treated with pyrimethamine and sulfa but not all patients tolerate side effects zIn the majority of cases this is due to reactivation of the chronic infection rather than new infection

32 Life cycle of T. gondii

33 Latent bradyzoite cysts confer life-long infection zCysts form in brain and skeletal muscle zBradyzoite cyst persist in the immune host zBradyzoites are resistant to all currently available drugs

34 Bradyzoite cysts are highly infective if ingested zBradyzoites (not tachyzoites) are resistant to low pH and digestive enzymes during stomach passage zProtective cyst wall is finally dissolved and bradyzoites infect tissue and transform into tachys zTachyzoites: pathogenesis, Bradyzoites: epidemiology

35 Intracellular parasitism zMacrophages are important “microbe killers”, however several pathogens have found ways to escape killing zTrypansoma cruzi -- induces phagocytosis and escapes into the cytoplasm zMycobacterium tuberculosis -- induce phagocytosis and block lysosomal maturation zLeishmania appears to thrive in a fully matured lysosome zToxoplasma was equally thought to induce phagocytosis and then some how block fusion - however, an active invasion model has gained wide acceptance

36 Host cell invasion Dr. Gary Ward University of Vermont


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