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Department of Surgery

Ayala Lab

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Ayala Lab

Dr. Ayala's research focuses on several areas; (1) the differential effects of sepsis on immune cell function, (2) the role of programmed cell death/apoptosis in immune dysfunction observed following hemorrhage and/or sepsis, and (3) the contribution immune and/or non-immune cell expression of co-inhibitory cell surface molecules/”check-point” protein expression contributes to the development of acute lung injury resultant from shock and/or septic insults.

Recently, the work in Dr. Ayala’s lab has centered on developing a better understanding of what the patho-physiological mechanisms of shock, tissue injury and/or sepsis have on the individual that lead to increasing their susceptibility to subsequent multiple organ failure.  Importantly, the lab has tried to do this through not only the application of what they believe are valuable pre-clinical animal models, but also through collaborative partnerships with clinician scientists here at Rhode Island Hospital and around the world, which can translate the significance of bench-side observations back to the critically ill patient.

Biography

Dr. Ayala is Professor of Surgery (Research) and the Director of the Division of Surgical Research at Rhode Island Hospital/the Alpert School of Medicine at Brown University. He has been recognized by his peers through election as a “Fellow”-American Association for the Advancement of Science (AAAS) (22’). He was a NIH-NIGMS-Consultant/Panel member for ‘National Advisory General Medical Sciences (NAGMS) Working Group on Sepsis’ (18'-19'). He served as a standing member of the National Institutes of Health (NIH)-Lung Cellular Molecular & Immunology (LCMI)-Study Section as well as previously on the NIH-Surgery Anesthesia Trauma (SAT)-Study Section, and has served as an ad hoc on various NIH site visit teams/SEPs/ad hoc review panels, the Veteran's Administration (VA)-Department of Defense (DoD) Merit Review Board, Wellcome Trust as well as Shriners Research Hospitals (over 12 years). He has been recognized by his peers through election to President (04'-05'), Treasurer (02'-04'), and Scientific Program Chairman (01) of the Shock Society; as selection as Recorder/Executive Council (05'-07') of the Surgical Infection Society, and by appointment to the Society of Leukocyte Biology council (11'-13'). Dr. Ayala was also the recipient of a "Maximizing Investigators' Research Award  (MIRA)" for Established Investigators (R35) from the NIH-NIGMS (16'); the Shock Society's 10th annual 'Scientific Achievement Award' (07'); and the 15th annual 'Distinguished Service Award' (09'). He has over 300 manuscripts/review articles to his credit and has been continuously funded by the NIH since 1991. He is also a member of the training faculty of the Brown University Graduate Pathobiology Program; the Therapeutic Sciences Graduate Program, the Department of Cell Biology, Molecular Biology & Biochemistry Graduate Program; and is an adjunct Professor/mentor in the Univ. R.I. graduate program in the Department of Cellular & Molecular Biology. During his tenure at Brown University and previously at Michigan State University he has had the privilege of mentoring students ranging from undergraduates and medical students to surgical residents, post-doctoral fellows and Junior Faculty.  Research interests include projects looking at: the differential effects of sepsis on immune cell function; the role of programmed cell death/ apoptosis in immune dysfunction observed following hemorrhage and/or sepsis; as well as, the contribution of 'checkpoint' protein/ accessory molecule expression to the pathological process mediating acute lung injury resultant from shock and/or septic insults.

Research Overview

Research interests include projects looking at: 1) determining how select expression of cell surface co-inhibitory proteins (checkpoint proteins) and their ligands, on innate immune cells as well as non-immune cells; alter the morbid events associated with adult sepsis.  2) Utilizing a novel model of indirect-acute lung (iALI) to ask how checkpoint protein expression affects the patho-mechanisms driving iALI.  Finally, 3) since the neonate possesses a unique/ naive immune system and is more susceptible to morbid response in the face of infectious challenge, we are examining if the expression of checkpoint protein family members have a comparative impact on the neonate's response to septic insult.

Research Statement

The work in our laboratory has centered on understanding the patho-physiological effects of shock/ tissue injury/ sepsis that lead to immune dysfunction and subsequent multiple organ failure in the critically ill trauma patient (through animal modeling and collaborative clinical studies). We have described, over the years, numerous deficits in both components of cell-mediated (T-cell, NKT-cell, gd T-cell, Treg-cell, ILC2, etc) and innate (macrophage, neutrophil, dendritic cells) immune responsiveness induced by shock or sepsis, which are underpinned by alterations in cell signaling, protein translation and transcription patterns. Particular emphasis has been directed at defining the role of soluble mediators (e.g., IL-4, IL-10, IL-16, IL-33, MCP-1, MIP-2/KC/IL-8, TGF-b, PGE2, NO, steroids, etc.), inhibitory receptors/checkpoint proteins (e.g., PD-1:PD-L1/L2, BTLA:HVEM, VISTA, FasL:Fas, etc.) and/or cellular pathways (e.g., p38 MAPKs, STATs, SOCS 1/3, Shp1/2, Rip1/3, NFkB, etc.) involved in orchestrating these changes in mouse models and critically ill patient. We have also found evidence of alterations of the immune cell's apoptotic process, present in these animals and are actively examining the contribution of this pathway. It is our hope that, by understanding the cellular/molecular mechanisms which control these alterations in the traumatized or septic animal/patient, we will improve our ability to treat them.

Major Theme of Research: injury, shock, organ dysfunction, immunology and infection

Laboratory Staff-Contact List (Rev: 6/16/2023):

Fellows

  • Chyna Gray, Ph.D.

    Chyna_Gray@brown.edu
    (401) 444-0381

    T32-Nat. Res. Serv. Award/
    Post-Doctoral Fellow
    Aldrich 244

Graduate Students

  • Brandon Armstead, B.S., M.S.

    Brandon_Armstead@brown.edu
    (401) 444-6482

    Grad. Pathol. prog.-Grad. Student
    Aldrich 226

  • Fernando Gutierrez-Garcia, B.S., M.S.

    Fernando_Gutierrez_Garcia@brown.edu
    (401) 444-6482

    Grad. Pathol. prog.-Grad. Student
    Aldrich 226

  • Habesha "Fasika" Petros, B.S.

    Habesha_Petros@brown.edu
    (401) 444-6706

    Master in Biotechnology prog.-Grad. Student
    Aldrich 242

Senior Research Assistant

  • Yaping Chen, B.S.

    YChen2@lifespan.org
    (401) 444-6728

    Sr. Res. Assist.
    Aldrich 228

Administrative

  • Courtney V. Coto, A.D. Med. Trans.

    CCoto@lifespan.org
    (401) 444-5157

    Admin. Assistant
    Aldrich 230

Undergrad/Medical Students

  • Denise Danielle Tamesis

    Denise_Danielle_Tamesis@Brown.edu

    Undergrad. Student
    Aldrich 223

Collaborators at Other Institutions: 

  • Linc L. Moldawer, Ph.D.
  • Ping Wang, M.D.
  • Craig M. Coopersmith, M.D.
  • Guillaume Monneret, Ph.D.
  • Mario Perl, M.D.
  • Silvia Uriarte, Ph.D.
  • Jianwen (Jen) Bai, M.D., Ph.D.
  • Fabienne Venet, Pharm.D., Ph.D.
  • Philip A. Efron, M.D.
  • Steven C. Katz, M.D.
  • Samithamby Jeyaseelan (Jey), D.V.M., Ph.D
  • Daniel Remick, M.D.
  • Adrian M. Piliponsky, Ph.D.

Laboratory Alumni (back to: 2000):

  • Priscilla Mickey Appiah
  • Emily Hensler, M.D.
  • Chung "Sunny" Lee, B.S.
  • John Davies
  • Elizabeth Tindal, M.D., M.P.H.
  • Ezequiel Cruz Rosa
  • Michelle E. Wakeley, M.D.
  • Yael Quiles-Ramirez
  • Destiny Arnold, B.A.
  • Jihong Jiang, M.D., Ph.D.
  • Baoji Hu, M.D., M.S.
  • Kaitlyn Petitpas, B.A.
  • Myles Bartholemew, B.S.
  • Eleanor Fallon, M.D.
  • Qian Yang, M.D., M.S.
  • Jessica Tolbert
  • Marilyn Le, M.S.
  • Ann-Lise Rosi, Ph.D., M.S.
  • Jiali Zhu, M.D.
  • Tristen Chun, M.D.
  • Craig Erickson, M.D.
  • Chyna Gray, B.S. 
  • Shumin Zhu, M.D., M.S.
  • Erlyana Clarke, B.S.
  • Whitney Young, M.D.
  • Valeria Sanabria Guillen, B.S.
  • Tianzhu Tao, M.D., M.S.
  • Tinting Cheng, M.D., M.S.
  • Santiago Pulido, B.S.
  • Xin Huang, M.D., Ph.D.
  • John Young, M.D.
  • Noelle Hutchins, M.S., Ph.D.
  • Youping Wu, M.D., M.S.  
  • Lunxian (Kelly) Tang, M.D., M.S.
  • Maude Kettenman, M.D., M.S.
  • Fei Wang, M.D., M.S.
  • Sam McNeal, Ph.D.
  • Nicholas Shubin, Ph.D.
  • Jianwen (Jen) Bai, M.D., M.S.
  • Gabriela Garcia, B.A.
  • Lydea Irwin, B.S.
  • Shivana Maharaj, B.A.
  • Sean Monaghan, M.D.
  • Eleanor (Ellie) Smith, B.S.
  • Ye Sul Kim, B.S.
  • Yvonne Wang, B.S., M.D.
  • Kim Tran, B.S. 
  • Yu (Tina) Zhao.
  • Mia Tran, B.S.
  • Josha Borgerding, B.S. 
  • Rajan Thakkar, M.D.
  • Sima Patel, B.S.
  • Nicholas Carter, B.A.
  • Sadella Santos, B.S.
  • Fabienne Venet, Ph.D., M.S., Pharm.D.
  • Arnaldo Carriera, B.S.
  • Ana Moreno, B.S.
  • Megan Garber, B.S., M.S.
  • Earl Campbell, III, B.S.
  • Brian J. Horner, D.O.
  • Ryan Swan, M.D.
  • Doreen Szollosi (maiden name: Wesche-Soldato), Ph.D.
  • Leia Foster, B.S.
  • Caroline Hu, B.A., M.S.
  • Mario Perl, M.D.
  • Ulrike (Uli) Perl, R.N.
  • Antonio Funches, B.S.
  • Tina Rachel, B.A., M.S.
  • Nicholas Winoski, B.A., M.D.
  • Ben Galen, B.S., M.D.
  • Lesley Doughty, M.D.
  • Rani Cooma-Ramberan, B.S.
  • Leslie Jones, B.S.
  • Sarah Newton (maiden name: Bray), B.A., M.D.
  • Rebecca Rhee, B.A., M.D.
  • Yanli Ding, D.D.S., Ph.D, D.M.D
  • Patricia S. Grutkoski, Ph.D.
  • Crystal Lane, B.S.
  • Grace Jarrar (maiden name: Song), M.D., B.A.
  • Watkins, B.A., Ph.D.
  • Amit R.T. Joshi, M.D., B.A.
  • Rory A. Priester, M.D., B.A.

Funded Research

Active Grant Support:

2016-2026
NIH-NIGMS Research Grant: "Mechanism of Immune Dysfunction and Morbid Outcome in Response to Shock/Sepsis."
Grant No.: R35 GM118097
Principal Investigator: Alfred Ayala
Total Support = $2,812,574 in direct & indirect cost (for 2021-2026).

NIH-NIGMS Administrative Supplement to Promote Diversity in Health-Related Research: "Mechanism of Immune Dysfunction and Morbid Outcome in Response to Shock/Sepsis."
Grant No.: R35 GM118097-07S1
Principal Investigator: Alfred Ayala
Total Support = $144,655 in direct & indirect cost (for 2022-2025).

2004-2025
NIH-NIGMS Post-Doctoral Training Grant: "Trauma-inflammation Research Training."
Grant No.: T32-GM08768
Program Director: Alfred Ayala
Executive Committee/Training Faculty: Alfred Ayala
Total Support Requested = $1,309,020 in direct and indirect cost (for 2020-2025).

Grants/Funding on which 'role' is other than Principal Investigator:

2018-2023
NCRR COBRE Grant: "CardioPulmonary Vascular Biology-COBRE:Endothelial
Cell Injury & Repair."
Grant No. P20-RR032693
Program Director: Sharon Rounds
Executive Committee/Mentor (for Sean Monahghan): Alfred Ayala
Total Support = $7,410,000 in direct and indirect cost (for 2018-2023).

2007-2022
NIH-NIHLBI Undergraduate Student Training Grant: "Short-term Training Program to Increase Diversity in Health-Related Research."
Grant No.: R25-HL088992
Principal Investigator: Elizabeth Harrington
Faculty Trainer/Exec. Comm.: Alfred Ayala
Total Support = $101,258 in direct and indirect cost annually.

2021-2026
NIH-NIGMS Research Grant:  "Improving Sepsis Care with Deep RNA Sequencing Data.”
Grant No.: R35-GM142638
Principle Investigator: Sean F. Monaghan
Collaborator: Alfred Ayala
Total Support Requested = $1,978,996 in direct and indirect cost (for 2021-2026).

Scholarly Work

Book Chapters

Chun, T.T., Potz, B.A., Young, W.A., Ayala, A.  2017.  Chapter 4: Overview of the Molecular Pathways and Mediators of Sepsis.  In: “Sepsis: Definitions, Pathophysiology and the Challenge of Bedside Management”; Edited by: Ward, N.S. & Levy, M.M.; Springer, Heidelberg, Germany, pg 47-69.

Monaghan, S.F., Ayala, A.  2016.  Part 14.3: Inflammationand the Host Response; Section 311: Adaptive Immunity in Critical Illness. In the “Oxford Textbook of Critical Care, 2nd Edition.   Editors: Webb, A., Angus, D., Finfer, S., Gattinoni, L., Singer, M. Oxford University Press, Oxford, UK.

Thakkar, R.K., Huang, X., Lomas-Neira, J., Heffernan, D., Ayala, A.  2011.  Chapter 5: Sepsis and the immune response, in: Essential Immunology for Surgeons, Edited by Eremin, O. & Sewell, H., Oxford University Press, Oxford, U.K. pg 303-342.

Chung, C.S., Swan, R., Wesche-Soldato, D.E., Perl, M., Ayala, A.  2009.  Apoptosis: in Sepsis and non-infectious SIRS.  In: Sepsis and Non-Infectious Systemic Inflammation.  Editors: J-M. Cavaillon & C. Adrie.  Wiley-VCH, WeinHeim, Germany, pg 205-229.

Wesche-Soldato, D.E., Lomas-Neira, J., Perl, M., Chung, C.S., Ayala, A. 2008.  Hydrodynamic Delivery of siRNA in a Mouse Model of Sepsis.  Chapter 5 in: Methods in Molecular Biology, volume 442: RNAi: Design and Application.  Editors: S. Barik.  Human Press Inc., Totowa, NJ, pg 67-73.

Ayala, A., Wesche-Soldato, D.E., Perl, M., Lomas-Neira, J.L., Swan, R., Chung, C.S.   2007.  Novartis Foundation Symposium No. 280 on Sepsis-New Insights, New Therapies. Chapter: Blockade of apoptosis as a rational therapeutic strategy for the treatment of sepsis.  Wiley Press, Chichester, U.K., pg. 37-52.

Grutkoski, P.S., Chung, C.S., Albina, J.E., Biffl, W.L., Ayala, A.  2004.  Chapter: 38. Apoptosis in the Critically Ill.   In: Textbook of Critical Care, 5th Edition.  Editors: Abraham, E.  W.B. Saunders Publishers, Philadelphia, PA, pg. 195-202.

Ayala, A., Chung, C.S., Song, G.Y., Grutkoski, P.S., Simms, H.H. 2002.  Chapter 3.  Down-Regulation of the Immune Response.  In: Molecular & Cellular Biology of Critical Care Medicine.  Editors: Linden, P. and Doughty L.A.  Kluwer Academic Publishers, Norwell, MA, pg 41-78.

Angele, M.K., Schwacha, M.G., Ayala, A., Chaudry, I.H.  2001.  The role of macrophages following hemorrhagic shock.  In: Shock, Editors: Z-Y Luo, C-S. Tang, H-M Gin.  TianGin Science and Technology Press. TianGin, China. 699-721.

Ayala, A., Wang, P., Chaudry, I.H.  2001.  Chapter 27: Shock Models: Hemorrhage. In: Surgical Research.  Editors: Souba, W., Wilmore, D.  Academic Press, San Diego, CA, pg 317-330.

Chung, C.S., Chaudry, I.H., Ayala, A.  2000.  The apoptotic response of the lymphoid immune system to trauma, shock and sepsis.  In: Yearbook of Intensive Care and Emergency Medicine-2000.  Editors: Vincent, J.L.  Springer-Verlag, Heidelberg, Germany pg 27-40.

Ayala, A., Chung, C.S., Song, G.Y.  1999.  Lymphocyte anergy, apoptosis and cell activation in polymicrobial sepsis.  In: Update in Intensive Care and Emergency Medicine, Vol. 31.  Editors: Marshal, J.C., Cohen, J., Vincent, J.L.  Springer-Verlag, Berlin, Germany, pg. 226-246.

Angele, M.K., Schwacha, M.G., Ayala, A., Chaudry, I.H.  1999.  The immunoinflammatory response to hemorrhage.  In: Sepsis and Multiple Organ Dysfunction.  Editors: Deitch, E.A., Windsor and J.L. Vincent.  Harcourt Brace & Co. Ltd., London, U.K., pg. 117-126.

Ayala, A., Chaudry, I.H.  1998.  Anti-cytokine strategies in peritonitis.  Is local, intra-abdominal, therapy possible?  In: Cytokines and the Abdominal Surgeon, Editor: M. Schein, Medical Intelligence Unit; R.G. Landes Company, Austin, TX. Pg.245-271.

Angele, M.K., Ayala, A., Chaudry, I.H.  1998.  Cytokine in experimental peritonitis. In: Cytokines and the Abdominal Surgeon, Editor: M. Schein, Medical Intelligence Unit; R.G. Landes Company, Austin, TX. Pg.107-116.

Zellweger, R., Ayala, A., Chaudry, I.H.  1998.  Predisposing factors: effect of sex, nutritional factors and age on the immunity following shock and sepsis.  In: Cytokines in Severe Sepsis and Septic Shock.  Editors: H. Redl and G. Schlag, Birkhauser Publishing Ltd., Basel, Switzerland, pg. 57-77.

Zellweger, R., Ayala, A., Wang, P., Chaudry, I.H.  1998.  Immunomodulation following shock and sepsis.  In: Cytokines in Severe Sepsis and Septic Shock.  Editors: H. Redl and G. Schlag, Birkhauser Publishing Ltd., Basel, Switzerland, pg. 313-295.

Chaudry, I.H., Wichmann, M.W., Ayala, A.  1997.  Immunological alterations following hemorrhagic shock: considerations for resuscitation with blood substitutes. In: Fundamental Principles and Clinical Applications of Red Blood Cell Substitutes, Editors, R. Rabinovici, G. Feuerstein, A.S. Rudolph, Marcel-Dekker, New York, pg.165-188.

Ayala, A., Wang, P., Chaudry, I.H.  1996.  Hemorrhage induced alteration in macrophage signal transduction.  In Immune Consequences of Trauma, Shock and Sepsis: Mechanisms and Therapeutic Approaches, Editor, E. Faist, Pabst, Berlin 84-98.

Chaudry, I.H., Ayala, A., Wang, P.  1996.  Early indicator of hepatocellular dysfunction in sepsis and hemorrhage.  In Immune Consequences of Trauma, Shock and Sepsis: Mechanisms and Therapeutic Approaches, Editor, E. Faist, Pabst, Berlin 935-947.

Chaudry, I.H., Wang, P., Ayala, A.  1996.  Hepatic and splenic macrophage response to shock.  In Immune Consequences of Trauma, Shock and Sepsis: Mechanisms and Therapeutic Approaches, Editor, E. Faist, Pabst, Berlin 130-141.

Chaudry, I.H., Zellweger, R., Ayala, A. 1995.  The role of bacterial translocation in kupffer cell immune function following hemorrhage.  In Bacterial Endotoxins: Lipopolysaccharides, From Genes to Therapy, Editor, E. Faist, Wiley-Liss, Inc., New York, pg 209-218.

Chaudry, I.H., Ayala, A., Meldrum, D., and W. Ertel.  1993.  Hemorrhage-induced alterations in cell-mediated immune function.  In Immune Consequences of Trauma, Shock and Sepsis: Mechanisms and Therapeutic Approaches, Editor, E. Faist, Springer-Verlag, Berlin, 149-159.

Stephan, R.N., Ayala, A., Chaudry, I.H.  1993.  Monocyte and lymphocyte responses following trauma.  In Pathophysiology of Shock, Sepsis and Organ Failure, Editor, G. Schlag and H. Redl, Springer-Verlag, Berlin, 131-139.

Book

Chaudry, I.H., Ayala, A.  Immunologic Aspects of Hemorrhage."  Medical Intelligence Unit; R.G. Landes Company, Austin, TX, October, 1992.

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