Principal Investigator/Program Director (Last, first, middle): Yuan, Sarah, YRESEARCH & RELATED Other Project Information1. * Are Human Subjects Involved? m Yes l No1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number2. * Are Vertebrate Animals Used? l Yes m No2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 11-04-2004 Animal Welfare Assurance Number A3433-013. * Is proprietary/privileged information m Yes l No included in the application?4.a.* Does this project have an actual or potential impact on m Yes l No the environment?4.b. If yes, please explain:4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No4.d. If yes, please explain:5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators?5.b. If yes, identify countries:5.c. Optional Explanation:6. * Project Summary/Abstract 371-Project_Summary.pdf Mime Type: application/pdf7. * Project Narrative 3745-Public_Health_Relevance.pdf Mime Type: application/pdf8. Bibliography & References Cited 3789-Bibliography.pdf Mime Type: application/pdf9. Facilities & Other Resources 9595-Facilities_Resources.pdf Mime Type: application/pdf10. Equipment 283-Equipment.pdf Mime Type: application/pdfTracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008Principal Investigator/Program Director (Last, first, middle): Yuan, Sarah, YPROJECT SUMMARY - ABSTRACTThermal injury represents a common form of trauma associated with significant mortality and morbidity.The end-organ effect of burn-induced systemic inflammation imposes a life-threatening problem evenafter successful initial resuscitation. One of the mechanisms underlying multiple organ failure ismicrovascular barrier dysfunction, a cellular process that has yet to be understood at the molecularlevel. The overall goal of this research project is to define the molecular mechanisms of microvascularleakage in thermal injury. Our initial investigation during the previous funding cycle has led to thedevelopment of unique experimental models that enable quantitative analyses of microvascularpermeability. The experiments revealed a series of signaling and structural modifications in theendothelial barrier involving the contractile cytoskeleton and cell-cell adhesive interactions. As acontinuing effort, we propose to extend this original investigation to a more in-depth analysis of theendothelial molecular response, with a practical view toward identifying new therapeutic targets for theeffective treatment of burn edema. Our hypothesis states that fluid leak during severe burn occurs viathe endothelial paracellular pathway caused by MLCK210-triggered actomyosin contraction and beta-catenin serine phosphorylation-induced VE-cadherin dissociation. Selective inhibition of the contractileelements and stabilization of junctional complexes possess therapeutic potential as alternative meansto attenuate the barrier injury. This hypothesis will be tested with a multifaceted approach thatintegrates novel cell biology techniques into physiological experiments. Through this study we wish toachieve the following specific aims: 1) to understand the molecular mechanisms of endothelial barrierdysfunction in thermal injury, and 2) to test the therapeutic effects of endothelial cytoskeleton-junctionstabilizers in treating burn edema. Information gleaned from the study will significantly advance ourunderstanding of microvascular pathobiology following thermal injury, with the potential to be translatedto clinical practice for improved patient care.Project Description Page 6
Showing the most recent 10 out of 21 publications
