FIELD OF STUDY (if applicable) Georgetown University, Washington, DC B.S. 05/02 Biology

Transcription

1 BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME Neal, Matthew David era COMMONS USER NAME (credential, e.g., agency login) nealmd POSITION TITLE Assistant Professor of Surgery and Critical Care Medicine Member, Vascular Medicine Institute EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) Georgetown University, Washington, DC B.S. 05/02 Biology University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, MD 05/06 Medicine 06/06-06/14 General Surgery Residency Postdoctoral 07/09-06/12 Inflammation and Innate Immunity 07/14-06/15 Surgical Critical Care Fellowship A. Personal Statement I am a surgeon-scientist with a clinical practice consisting of trauma, emergency general surgery, and surgical critical care as well as a translational research interest in coagulopathy in the setting of injury. My basic science laboratory focuses on understanding the mechanisms of hemostasis and coagulation following trauma and hemorrhagic shock with a specific interest in the impact of sterile inflammation on platelet function. Uncontrolled hemorrhage is the leading cause of preventable death in trauma, which accounts for nearly 10% of annual mortality worldwide. Over 25% of severely injured patients will present with impaired coagulation which increases morbidity and mortality. Venous thromboembolic events are a common late sequelae of this coagulopathy and are a leading cause of morbidity and mortality after trauma. Although it is well known that trauma results in a profound inflammatory response driven by innate immune activation, the mechanisms of this acute coagulopathy of trauma are poorly understood. Our lab has recently discovered a potential link between sterile inflammation and impaired coagulation through expression of the innate immune receptor, tolllike receptor 4 (TLR4) and the endogenous danger signaling molecule, high mobility group box 1 protein (HMGB1) on platelets. We are testing multiple drug targets for regulating HMGB1 release and attenuating platelet dysfunction following trauma. We also have an interest in targeted platelet therapy and have begun to devise novel platelet specific nanotechnology for drug delivery. We have a multi-disciplinary collaboration combining international experts in platelet biology, coagulopathy, cellular imaging, nanotechnology, biomedical engineering, and innate immune signaling. In addition, I serve as a Co-Investigator for the Trans-agency Consortium to Investigate Trauma Induced Coagulopathy (TACTIC), a multi-center research investigation funded by the NIH to investigate the mechanisms of coagulopathy and inflammatory injury following trauma. My expertise and track record in collaborative endeavors provide the framework for necessary for successful completion of the proposed studies. 1

2 B. Positions and Honors Positions and Employment Intern, General Surgery, University of Pittsburgh Medical Center, Resident, General Surgery, University of Pittsburgh Medical Center, Postdoctoral Research Fellow, Laboratory of David J. Hackam MD, PhD, Senior Resident, General Surgery, University of Pittsburgh Medical Center, Administrative Chief Resident, General Surgery, University of Pittsburgh Medical Center, Fellow, Surgical Critical Care, University of Pittsburgh Medical Center, 2015-present Assistant Professor of Surgery and Critical Care Medicine, Department of Surgery, University of Pittsburgh School of Medicine 2015-present Member, Vascular Medicine Institute, University of Pittsburgh Other Experience and Professional Memberships Sigma Xi Scientific Society Pennsylvania Medical Society Allegheny County Medical Society American College of Surgeons Alpha Omega Alpha Shock Society Association for Academic Surgery Honors 1. Philip Troen, MD Excellence in Medical Student Research Mentoring Award, University of Pittsburgh School of Medicine, (2015 and 2016) 2. Fellow of the Year Award, University of Pittsburgh Medical Center, Department of Critical Care Medicine, (2015) 3. American Heart Association Fellow s Research Day First Prize, (2015) 4. Dorothy Maxwell Research Award, UPMC Department of Surgery (2014) 5. Appointed Administrative Chief Resident, UPMC Department of Surgery (2013) 6. Simmons Research Symposium Award for Most Outstanding Presentation, Richard L. Simmons Annual Research Day, Department of Surgery, UPMC (2012) 7. Simmons Research Symposium Second Place Award, Richard L. Simmons Annual Research Day, Department of Surgery, UPMC (2011) 8. American College of Surgeons Committee on Trauma, Runner-up, National COT Research Competition, Washington DC (2011) 9. Raymond H. Alexander Award, Most Outstanding Presentation, Eastern Association of the Surgery for Trauma (EAST) (2011) 10. American College of Surgeons Region III, Best Presentation (2010). 11. Pennsylvania Trauma Foundation: Best Resident Oral Presentation (2010) 12. Simmons Research Symposium Award for Most Outstanding Presentation, Richard L. Simmons Annual Research Day, Department of Surgery, UPMC (2010). 13. Susman Award, Most Significant Manuscript in Surgical Infection, 30 th Annual Surgical Infection Society Meeting, Las Vegas, Nevada (2010) 14. Wyeth Scholarship of the American College of Surgeons for the Study of Inflammation ( ) 15. Resident Research Award, Plenary Session Presentation, AAS Annual Meeting (2010) 16. American College of Surgeons Region III COT Best Oral Presentation (2008) 17. Pennsylvania Trauma Foundation: Best Resident Oral Presentation (2008) 18. Alpha Omega Alpha (AOA) (2006) 19. Graduated cum laude, top 10%, University of Pittsburgh School of Medicine (2006) 20. William K. Sieber, MD Award for Best Student in Pediatric Surgery, University of Pittsburgh School of Medicine (2006) 2

3 21. Pittsburgh Surgical Society Award for the Top Student in Surgery, University of Pittsburgh School of Medicine (2006) 22. Edward G. Curtiss Leadership in Service Award, University of Pittsburgh School of Medicine (2006) 23. First Place Award, Surgical Infection Society Resident/Fellow Presentations, 24 th Annual Meeting, Indianapolis, Indiana (2004) 24. Alpha Omega Alpha Student (AOA) Research Award (2004) 25. Arthur Mirsky Student Research Award, Most Outstanding Biomedical Research Project, University of Pittsburgh School of Medicine (2003) 26. Dean s Fellowship for Biomedical Research, University of Pittsburgh School of Medicine (2003) 27. Hilda M. Willis Scholarship, University of Pittsburgh School of Medicine ( ) 28. Chapman Award for Excellence, Most Outstanding Honors Thesis, Department of Biology, Georgetown University (2002) C. Contributions to Science and Selected Publications (from 41 total): 1. Investigating the role of innate immune signaling in platelet dysfunction and coagulopathy following trauma and hemorrhagic shock. My laboratory focuses on the merciless problem of the acute coagulopathy of trauma, which I face regularly in my clinical practice. This unique, endogenous coagulopathy presents in over 25% of severely injured patients and is a major contributor to morbidity and mortality. My lab seeks to define the molecular mechanisms that govern this coagulopathy. As a result of my training in innate immunity and inflammation, the lab is now focused on understanding the role of inflammatory signaling on platelets as a bridge between hemostasis and inflammation. My lab has recently discovered that platelets become excessively activated following sterile injury and contribute to the pathogenesis of acute lung injury and liver injury following hemorrhagic shock. In a manuscript recently published in the Journal of Clinical Investigation (JCI), we further have defined the molecular signaling pathways, including HMGB 1, TLR4, and critical downstream signaling molecules. Our lab collaborates extensively with a group of international platelet experts, and well as local authorities in platelet biology and advanced biological imaging techniques. This preliminary work provides the potential for identification of novel therapeutic targets to attenuate platelet dysfunction and regulate coagulopathy following injury. I served as the principal investigator and senior author for these studies. a. Vogel S, Bodenstein R, Chen Q, Feil S, Feil R, Rheinlaender J, Schäffer TE, Bohn E, Frick JS, Borst O, Münzer P, Walker B, Markel J, Csanyi G, Pagano PJ, Loughran P, Jessup ME, Watkins SC, Bullock GC, Sperry JL, Zuckerbraun BS, Billiar TR, Lotze MT, Gawaz M, Neal MD. Platelet derived HMGB1 is a critical mediator of thrombosis. Journal of Clinical Investigation. J Clin Invest Dec 1;125(12): b. Ding N, Chen G, Hoffman R, Loughran PA, Sodhi CP, Hackam DJ, Billiar TR, Neal MD. TLR4 Regulates Platelet Activation and Contributes to Coagulation Abnormality and Organ Injury in Hemorrhagic Shock and Resuscitation. Circulation: Cardiovasc Gen Oct:7(5): Clinical outcomes in coagulopathy, massive transfusion, trauma resuscitation, and emergency general surgery. As part of a clinical and translational focus to my research interest in coagulopathy, I have collaborated with multiple investigators locally and nationally to investigate outcomes in coagulopathy and patients undergoing massive transfusion and trauma resuscitations. These clinical outcomes studies focus on modifiable risk factors and resuscitation strategies in an attempt to minimize secondary organ injury following trauma. I also serve as a Co-Investigator on the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) Trial, which is a multicenter randomized controlled trial studying the pre-hospital administration of tranexamic acid in trauma patients and is funded by the Department of Defense. a. Neal MD, Moore HB, Moore EE, Freeman K, Cohen MJ, Sperry JL, Zuckerbraun BS, Park MS and TACTIC Investigators. Clinical Assessment of Trauma Induced Coagulopathy and Its Contribution to Post-Injury Mortality: A TACTIC Proposal. Journal of Trauma and Acute Care Surgery

4 Sep;79(3): b. Brown JB, Guyette FX, Neal MD, Claridge JA, Daley BJ, Harbrecht BG, Miller RS, Phelan HA, Adams PW, Early BJ, Peitzman AB, Billiar TR, Sperry JL. Taking the Blood Bank to the Field: The Design and Rationale of the Prehospital Air Medical Plasma (PAMPer) Trial. Prehosp Emerg Care Jul- Sep;19(3): PMID: c. Brown JB, Neal MD, Guyette FX, Peitzman AB, Billiar TR, Zuckerbraun BS, Sperry JL. Design of the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) Trial: Addressing the Knowledge Gaps. Prehosp Emerg Care January-March;19(1): PMID: d. Neal MD, Brown JB, Moore EE, Cuschieri J, Maier RV, Minei JP, Billiar TR, Peitzman AB, Cohen MJ, Sperry JL. Prehospital Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is Associated with a Reduced Incidence of Trauma-Induced Coagulopathy. Ann Surg Jan 13 [Epub ahead of print] 3. Understanding the role of innate immune signaling in the pathogenesis of intestinal inflammation and targeted innate immune drug development. During my medical school training and subsequent post-doctoral research fellowship, I studied the role of the critical innate immune receptor, Toll-like receptor 4 (TLR4), in the pathogenesis of necrotizing enterocolitis (NEC) under the mentorship of David J. Hackam, MD, PhD. NEC is a leading cause of morbidity and mortality in the premature infant, and during my time in the Hackam lab, I investigated the mechanisms by which TLR4 regulates intestinal inflammation and leads to organ injury in NEC. Specifically, I studied the role of TLR4 in the regulation of intestinal epithelial cell migration as regulated by autophagy as well as the control of intestinal proliferation through TLR4 regulation of intestinal stem cells. Through an in silico screening process, we identified potential candidate drugs as TLR4 inhibitors and documented successful resolution of NEC in a murine model as well as decreased inflammatory signaling in human tissue from babies with NEC with a candidate drug. I am a co-inventor on a United States Patent (#9,072,760), and a lead compound from this patent work is under consideration for FDA approval for clinical trials. I served as the primary investigator in all of the below-mentioned studies. a. Neal MD, Jia H, Eyer B, Good M, Guerriero C, Sodhi CP, Afrazi A, Prindle T, Ma C, Branca M, Ozolek J, Brodsky J, Wipf P, Hackam DJ. Discovery and Validation of a New Class of Small Molecule TLR4 Inhibitors. PLoS One Jun 12;8(6):e b. Neal MD, Sodhi CP, Dyer M, Craig BT, Good M, Jia H, Yazji I, Afrazi A, Richardson WM, Beer-Stolz D, Prindle T, Grant Z, Branca MF, Ozolek J, Hackam DJ. A Critical Role for Toll-like Receptor-4 Induction of Autophagy in the Regulation of Enterocyte Migration and the Pathogenesis of Necrotizing Enterocolitis. J Immunol Apr 1;190(7): c. Neal MD, Sodhi CP, Dyer M, Egan C, Good M, Afrazi A, Yazji I, Ma C, Branca M, Grant Z, Prindle T, Hackam DJ. Toll-like Receptor 4 is Expressed on Intestinal Stem Cells and Regulates Their Proliferation and Apoptosis through the p53 Upregulated Modulator of Apoptosis. J Biol Chem Oct 26;287(44): d. Neal MD, Leaphart C, Billiar TR, Levy R, Prince J, Schreiber A, Ford HR, Hackam DJ. Toll like receptor 4 (TLR4) mediates the phagocytosis of gram negative bacteria by intestinal epithelial cells. J Immunol Mar 1;176(5): Cover 4. Regulation of intestinal development and peri-natal signaling in necrotizing enterocolitis. Through collaborative efforts with other members of the Hackam lab, we studied the role of TLR4 in gut development as well as differential signaling of TLR4 in the fetal and post-natal intestine. Through these efforts, we identified that amniotic fluid contains potent regulators of TLR4 and contributes to intestinal development. In particular, our lab was the first to identify that TLR4 signaling regulates lineage development in the intestinal epithelium, 4

5 and these studies went on to show that regulating TLR4 (including using the compounds under patent review mentioned above) could attenuate the severity of and potentially prevent NEC through pre-natal delivery. These exciting collaborative efforts continue with the Hackam lab as they seek to develop a cure for this devastating disease. a. Yazji I, Sodhi CP, Lee EK, Good M, Egan CE, Afrazi A, Neal MD, Jia H, Lin J, Ma C, Branca MF, Prindle T, Richardson WM, Ozolek J, Billiar TR, Binion DG, Gladwin MT, Hackam DJ. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via enos-nonitrite signaling. Proc Natl Acad Sci Jun 4;110(23): b. Sodhi CP, Neal MD, Sho S, Good M, Siggers R, Russo AM, Branca M, Ma C, Prindle T, Hackam DJ. A Critical Role for Intestinal Epithelial TLR4 in Goblet Cell Differentiation and the Pathogenesis of Murine Necrotizing Enterocolitis. Gastroenterology Sep;143(3): e5. Cover c. Good M, Siggers RH, Sodhi CP, Afrazi A, Alkhudari F, Neal MD, Yazji I, Jia H, Branca M, Ma C, Prindle T, Grant J, Shah S, Slagle D, Paredes J, Ozolek J, Gittes GK, Hackam DJ. Amniotic Fluid Inhibits Toll Like Receptor 4 Signaling in the Fetal and Neonatal Intestinal Epithelium. Proc Natl Acad Sci Jul 10;109(28): d. Afrazi A, Sodhi CP, Jia H, Good M, Yazji I, Neal MD, Branca M, Prindle T, Hackam DJ. Heat Shock Protein-70 (HSP-70) Negatives Regulates TLR4 in the Pathogenesis of Necrotizing Enterocolitis. J Immunol May 1;188(9): Cover Complete list of published works in MyBibliography: D. Research Support Ongoing Research Support Grant information: American Association for the Surgery of Trauma (AAST) Research and Education Foundation Scholarship Title: Platelet derived HMGB1 regulates thrombosis following trauma Years inclusive: Grant information: Vascular Medicine Institute Pilot Project Program in Hemostasis and Vascular Biology (P3HVB) Title: Platelet derived HMGB1 regulates thrombosis and organ injury following trauma and hemorrhagic shock Years inclusive: Grant information: Janssen Investigator Initiated Study (Industry sponsored) Title: Utilization of thromboelastography to monitor Rivaroxaban activity in trauma and emergency surgery Years inclusive: Grant information: UM1HL (Mann, Esmon, Wisniewski (PIs)) Title: Analysis and Characterization of Trauma-Induced Coagulopathy Role in project: Co-Investigator Years inclusive: