Montclair State University Department of Spanish and Italian
4
pages
English
Documents
Le téléchargement nécessite un accès à la bibliothèque YouScribe Tout savoir sur nos offres
4
pages
English
Documents
Le téléchargement nécessite un accès à la bibliothèque YouScribe Tout savoir sur nos offres
- cours magistral
- mémoire
- cours - matière potentielle : progresses
- cours - matière potentielle : management system
- exposé
- leçon - matière potentielle : proficiency
- cours - matière potentielle : requirements
- cours - matière potentielle : materials
- tempo sufficiente per una prima
- living spaces
- che cosa consistono
- luoghi della letteratura italiana
- g.nava
- disposizione del corso
- acquisto delle traduzioni
- intensive course
- film
- course
The HTS FOAs DeconstructedHigh Throughput Assistance for PAR-12-058 and -059 Grant Applications (Solicitation of Assays for High Throughput Screening (HTS) to Discover Chemical Probes (R01)) The University of Michigan Center for Chemical Genomics (CCG) in the Life Sciences Institute is an ideal partner for biomedical researchers interested in using high throughput screening (HTS) to identify chemical probes through the recently announced NIH funding opportunities. Our core is led and staffed by scientists with extensive industry and academic experience in assay development/miniaturization, high throughput screening (HTS), hit selection and validation. The CCG works also closely with the Vahlteich Medicinal Chemistry Core (VMCC) and PK core to support Michigan Drug Discovery. Basic Questions•When are the submission deadlines? Standard NIH Deadlines apply o New RO1 deadlines – February 5, June 5, October 5 New R21 deadlines – February 16, June 16, October 16 AIDS-related deadlines – May 7, December 7, January 7 •Is there an earlier deadline for the letter of intent? Yes – 30 days prior to anticipated application due date – asked for but not required – see FOA o Description/Technical Requirements •Fund opportunities for investigators to translate knowledge about diseases into tangible tools for translational research•Collaboration between investigators and established academic, nonprofit, or commercial HTS facilities for the purpose of discovering and developing small molecule chemical probes1) Discoveryand development of novel, small molecules for their use in studying disease treatment relevant to the participating NIH institute 2) Discoveryand/or validation of novel, biological targets that will inform studies of disease mechanism •New assay development is outside the scope of these FOAsThese FOAs direct investigators to PA-10-213 : Development of Assays for High Throughput o Screening for use in Probe and Pre-therapeutic Discovery (R01)•Investigator should have:Disease target relevant to funding agencyo Clearly define the overall goals for the use of the assay and discovered probesWhat new insights into the disease target/process will be gained?An HTS-ready assayo Demonstrated reproducibility in a low-to-moderate throughput setting•Predictable and reproducible responses to known control compounds or conditions providing a clear threshold between positive and negative responses. Aim for high S:B, good reproducibility and reliability (Z’ > 0.5)•Having initial pilot screen data is suggested (a few hundred compounds, such as the FDA Approved Drugs or other Bioactive Molecule library)
•Proven reagent availability/capacity for the size of the screenFollow-up assays in placeo Demonstrate the ability and suitability of secondary and counter screen assays to be used during and after the HTS campaignShould demonstrate a clear plan for evaluating the significance of the hits obtained in the primary screen. Follow-up should be able to accommodate multiple hit compounds.•HTS facility should have:A large, diverse compound collectiono Robotics and expertise to optimize and implement the assayso Chemo-Informatics to interpret the results and publicly share the data in PubChemo Synthetic and medicinal chemistry resources for minor optimization and hit validationo he UM CCG and VMCC are well positioned to meet all of these requirements oT •The following fall under the NIH’s definition of a “validated hit” and demonstrate readiness for application for funding under PAR-12-060 - Solicitation of Validated Hits for the Discovery ofin vivoChemical Probes (RO1).oMust elicit a reproducible response in at least two assay typesMust also elicit a dose-response over a hundred-fold concentration rangeo Must be analytically validated for integrity and purityo Through resynthesized powder, for exampleMust demonstrate adequate potencyo oMust possess a tractable starting point of chemical optimization with no obvious major chemical liabilitiesen possible, multiple series of scaffolds may be submitted for parallel optimizationoWh Document Specifications •What special sections and/or statements are required? Must include a statement of willingness to deposit the assay data, protocols and structures to o PubChem with the Data Sharing section of the application (include in the Resource Sharing Plan) oLetter of Support/Collaboration from HTS center (e.g. UM CCG) Narrative Structure •To follow best in the language of the FOA, the following headings/subheadings could be used to organize your narrative. •Two stages of discovery research are included in these FOAs. These would make 2 nice specific aims. HTS Implementation o How much assay adaptation to the screening center will be needed?This will depend upon whether or not you already have pilot screening dataPilot screening data can be used to demonstrate assay performanceThis may include a small component of library optimization (biology-oriented chemical synthesis) or virtual screening with a goal of improving screening success likelihoodHit Validation o Fresh compound samples of initial hits selected for further confirmation.Implementation of secondary assays to remove false positives and/or validate targetAdvanced chemoinformatics analysis and medicinal chemistry inspection to triage the hit setPurchase and testing of fresh powder samples and related analogsVerification of compound structures
Extensive medicinal chemistry follow-up is outside the scope of these FOAs; investigators are directed towards PAR-12-060 - Soliciation of Validated Hits for the Discovery ofin vivoChemical Probes (RO1).•The FOAs list the following Technical Prerequisites – These fit great into an “Approach” section. Preliminary data can go here. oCompound CollectionUM CCG maintains the following library types: •large, diverse compound libraries •small, focused compound libraries •large, diverse natural product extract libraries •complete or subset RNAi libraries Primary HTS Assayo In general, want an assay with an adequate detection principle that allows for the detection of weak binders with acceptably low rates of false positives and negatives In general, want addition of reagents (without the need for washing) and endpoint measurements. See the FOAs or search PubChem Bioassay to view a long list of traditionally acceptable HTS assay types. The UM CCG can accommodate the following detection methods listed in the FOA: •Fluorescence •Luminescence •Absorbance •FRET and TR-FRET •Flow cytometry •Fluorescence imaging •BRET •AlphaScreen •Biophysical Assays (for example, for Protein-Protein Interactions) oFollow-Up AssaysDemonstrate the cascade of assays in place to remove false positives and prioritize hits See the FOAs or search PubChem Bioassay to view a long list of counter-screen ideas. •The FOAs list the following Programatic Guidelines Programmatic Management of Screening Projecto A team composed of the screening staff, the assay submitter, and an NIH program staff will compose a Chemical Probe Development Plan (CPDP) at the beginning of the awarded research project. Here, the specific criteria that a compound must meet to be considered a probe are defined and a flowchart summarizing the critical path to probe discovery is created. Awardees will work with the NIH PubChem staff to ensure fidelity of the data shared with the public and to submit annual probe progress reports. Data Sharingo The data generated under this FOA are expected to be released to PubChem 1) Primaryassay data from HTS 2) Datagenerated in the follow-up assays 3) Protocolsfor assays implemented 4) Chemicalstructure of the compounds tested
The UM CCG has registered its compound libraries with PubChem and can assist in the required data sharing of assay results •The FOA uses the standard review criteria Overall Impact with scoring criteria consisting of Significance, Investigator(s), Innovation, o Approach and Environment Sample Proposal An example of a successful screening grant proposal is available to UM users upon request.
