This K-23 award will provide an opportunity for Dr. Watkins to develop as an independent scientificinvestigator in the field of clinical and translational research, investigating the risk factors, and potentiallycausal factors, which explain the relationship between blood transfusion and trauma-associated acute lunginjury (ALI). This will be accomplished through an integrated curriculum consisting of coursework inepidemiology and biostatistics; intensive mentoring by local experts in the complications of severe trauma,ALI biology, and transfusion medicine; and practical experience in designing, conducting, and interpreting aclinical research project. Dr. Watkins will use this award to become an independently funded clinicalinvestigator with skills in advanced multivariate statistical methods and in the design of clinical andtransitional studies which include planned biologic sampling strategies necessary for biomarker discoveryand future gene expression studies. Moreover, he will gain an ability to design and implement clinicallyfocused projects which translate basic science advances into clinical practice, and also translate observedclinical associations into new basic science studies focusing on organ injury mechanisms. This will lead to asuccessful independent research career focused on understanding the clinical and biologic role of bloodtransfusion in the development of trauma-associated ALI and other trauma-related organ dysfunction. Theprimary scientific goal of this proposal is to determine the role of blood product storage time and cell-derivedmicroparticles in the development of trauma-associated ALI. To achieve this goal Dr. Watkins will: I.)establish the relationship between the storage time of transfused red blood cells and the development oftrauma-associated ALI in severely injured patients requiring transfusion, II.)compare the quantity of cell-derived microparticles within donor blood that is transfused to patients who subsequently develop, versus donot develop, trauma-associated ALI, and III.)obtain blood samples from a well-defined, severely injuredtrauma patient phenotype and: A.) use these samples to determine the associations between circulating cell-derived microparticles, transfusion, and trauma-associated ALI, and B.) establish an RNA repository fromcirculating leukocytes which will be archived for future studies aimed at identifying gene expression patternsassociated with blood transfusion and with trauma-associated ALI. This project has important implications forthose with severe trauma. The identification of potentially causal and modifiable factors important to thedevelopment of ALI could translate into novel biomarkers or new blood product storage, processing, ortransfusion guidelines. The goal of the microparticle studies is to reveal novel mechanisms of disease,opening new avenues for basic study. Finally, the identification of modifiable factors showing promise inpreventing trauma-associated ALI could be tested as interventions in future randomized clinical trials.PERFORMANCE SITE(S) (organization, city, state)University of WashingtonHarborview Medical CenterSeattle, WAPuget Sound Blood Center (Benaroya Research Institute)Seattle, WAPHS 398 (Rev. 04/06) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Watkins, Timothy R.KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below.Start with Principal Investigator(s). List all other key personnel in alphabetical order, last name first.Name eRA Commons User Name Organization Role on ProjectWatkins, Timothy R. watkins2 University of Washington Principal InvestigatorHudson, Leonard D. lenhudson University of Washington MentorOTHER SIGNIFICANT CONTRIBUTORSName Organization Roje on ProjectCuschieri, Joseph University of Washington CollaboratorGernsheimer, Terry University of Washington/Puget Collaborator/Transfusion Training Sound Blood CenterLopez, Jose A. University of Washington/Puget Collaborator/Advisor Sound Blood CenterMaier, RonaldV. University of Washington Collaborator/AdvisorMartin, Thomas R. University of Washington Collaborator/AdvisorPsaty, Bruce M. University of Washington AdvisorWurfel, Mark M. University of Washington CollaboratorHuman Embryonic StemCells [3 No D Yes .If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list:http://stemcells.nih.gov/reqistrv/index.asp. Use continuation pages as needed. . .If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used.Cell LinePHS 398 (Rev. 04/06) Page 3 Form Page 2-continuedNumber the following pages consecutively throughoutthe application. Do not use suffixes such as 4a, 4b.CDA TOC Substitute Page Candidate (Last, first, middle): Watkins, Timothy R.Use this substitute page for the Table of Contents of Research Career Development Awards. Type the name of the candidate at thetop of each printed page and each continuation page. RESEARCH CAREER DEVELOPMENT AWARD , TABLE OF CONTENTS (Substitute Page)Page NumbersLetters of Reference* (attach unopened references to the Face Page)Section I: Basic Administrative DataFace Page (Form Page 1)Description, Performance Sites, Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells (Form Page 2) 2-3Table of Contents (this CDA Substitute Form Page 3)-Budget for Entire Proposed Period of Support (Form Page 5) '. 5-7Biographical Sketches (Candidate, Sponsorfs],* Key Personnel and Other Significant Contributors* -Biographical Sketch Format page) (Notto exceed four pages) 8-41Other Support Pages (not for the candidate) 42_Resources (Resources Format page) ; 43-44Section II: Specialized InformationIntroduction to Revised/Resubmission Application* (Not to exceed 3 pages)1. The Candidate 45 A. Candidate's Background 45-47 B. Career Goals and Objectives: Scientific Biography [.... (Items A-D includedin 25page limit). 47-48 C. Career Development/Training Activities during Award Period 48-51 D. Training in the Responsible Conduct of Research 51-522. Statements by Sponsor, Co-Sponsor(s),* Consultant(s),* and Contributor(s)*. 53-723. Environment and Institutional Commitment to Candidate A. Description of Institutional Environment 73-74 B. Institutional Commitment to Candidate's Research Career Development 74-754. Research Plan A.
Specific Aims 7 6_ B. Background and Significance L^ (Items A-D includedin 25page limit) 76-83 C. Preliminary Studies/Progress Report 83-89 D. Research Design and Methods 89-100 E. Human Subjects Research : '.: 100-104 Targeted/Planned Enrollment Table (for new and continuing clinical research studies). 103 F. Vertebrate Animals NA G. Select Agent Research NA H. Literature Cited 104-112 I. Consortium/Contractual Arrangements* NA J. Resource Sharing NAChecklist. 113Appendix (Five collated sets. No page numbering necessary.) Check if Appendix is includedNumber of publications and manuscripts accepted for publication (not to exceed 5)List of Key Items: Note: Font and margin requirements must conform to limitsprovided in the Specific Instructions.'Include these items only when applicable. CITIZENSHIPf^ U.S. citizen or CD Permanent resident of U.S. (If a permanent resident of the U.S., a I I Non-citizen with temporary visanon-citizen national notarized statement must be provided by the time of award.) (Applicable for only the K99 program)PHS 398 (Rev. 04/06) Page 4 CDA Substitute Form Page 3
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