NIH T32 Research Training: Host Response to Trauma

Traumatic injury is the leading cause of death in the United States in individuals under the age of 44 years. More than 100,000 deaths each year in the United States alone are attributed to trauma. With the advent of new technologies and strategies to resuscitate, stabilize, and transport trauma patients, individuals are now surviving insults that in years past would have been lethal. This sets the stage for an often prolonged series of complications that may subsequently lead to death for reasons other than the original traumatic injury. A greater understanding of the biological mechanisms of traumatic injury and its complications may lead to the development of new diagnostics, treatment modalities and patient care practices.

Our trauma training program is designed to directly investigate those mechanisms. Our program is unique in that it involves numerous clinicians and scientists from multiple departments that offer a tremendous breadth of expertise and perspective. Trainees devote 2-3 years to conduct research on a topic related to trauma, burns or perioperative injury. In addition, didactic training is provided in the responsible conduct of research and research ethics and additional topics as necessary. The training program is entering its 30th year and to date has trained over 44 individuals, many of which have gone on to successful academic careers.

Our program welcomes applicants from underrepresented minorities and those with disabilities.  For additional information please visit here and here.

Program Faculty

Charles C. Caldwell, PhD Professor, Department of Surgery

The goal of our lab is to manipulate the immune response to sepsis in a manner that reduces tissue injury and mortality.  A key aspect of the high mortality associated with sepsis is the inappropriate immune response to the systemic infection.  The process of inflammation is instrumental to an organism’s response to invading microorganisms or repair of damaged tissues.  This process is initiated by components of the innate immune system and is tempered by a number of regulatory mechanisms.  If this hyper-inflammatory process is prolonged and/or exaggerated, significant inflammatory tissue and organ damage may ensue.  In contrast, suppression of the immune response prior to complete pathogen eradication can lead to bacterial overgrowth and organ failure. Our lab has three interlocking research interests: 1) elucidation of underlying mechanisms that mediate inflammation during sepsis, 2) determination of the septic patients' immune status, and 3) intervention with molecular analogs to alter the immune response.  Specifically, during sepsis, we are currently investigating 1) the role of T cells and neutrophil-derived microparticles and 2) the use of flow cytometry to determine patient immune status in a time-constrained environment.

Michael D. Goodman, MD Associate Professor, Department of Surgery

Our lab is focused on the systemic responses to injury, and more specifically, traumatic brain injury. The primary theme of this line of research focuses on the effects of brain injury on coagulation and inflammation and examines the interaction of these two responses. A secondary theme of this work, done in collaboration with the United States Air Force, focuses on the response to hypobaric and hypoxic environments following traumatic brain injury and polytrauma. To this end, we have established models of traumatic brain injury, hemorrhagic shock, and tissue injury to further examine the physiologic responses to secondary insults following primary injuries.  Additional laboratory projects are examining the roles of platelet activation and platelet-derived microvesicles after traumatic injuries, including hemorrhagic shock, traumatic brain injury, splenectomy, and a combination of these injuries, which are established in both basic science and translational models.

Erich Gulbins, MD, PhD Chair, Department of Molecular Biology, University of Duisburg-Essen Professor, Department of Surgery, University of Cincinnati

My laboratory studies the role of the acid sphingomyelinase/ceramide system in biomedicine. Currently, my lab is investigating the function of the acid sphingomyelinase/ceramide/acid ceramidase/sphingosine system in bacterial infections, tumor biology and cellular stress responses. In particular, we investigate the role of the acid sphingomyelinase, ceramide, acid ceramidase and sphingosine in pulmonary and systemic infections with Pseudomonas aeruginosa, Staphylococcus aureus and Mycobacteria (BCG). Mechanistic insights are applied to cystic fibrosis, ventilation-associated pneumonia and bacterial sepsis. Novel strategies to prevent these illnesses or treatments options are actively developed. Many cellular signalling events that are activated in response to bacterial pathogens are also involved in the response of the microenvironment to a malignant tumor. The group therefore studies the role of the acid sphingomyelinase/ceramide/acid ceramidase system in cells of the microenvironment of malignant tumors for their growth and treatment response. Finally, we are interested in understanding the role of sphingolipids in cellular stress responses. We study the signalling events initiated in mammalian cells by various forms of stress and applies these basic studies to the regulation of cell death.

David A. Hildeman, MD Professor, Department of Pediatrics, Immunology, CCHMC

Our lab studies the molecular mechanisms underlying T cell homeostasis in health and disease. Using gene-deficient simulation models, we have made seminal observations on the role of the proapoptotic molecule Bim in the control of the apoptotic “crash” of T cell responses. Further, our lab has shown the critical role of a common-gamma-chain cytokine/STAT5/Bcl-2 network acting to antagonize Bim and promote CD8+ effector and memory T cell survival. Current work in the lab focuses on (i) manipulation of autoimmune responses using small molecule Bcl-2 family member antagonists; (ii) epigenetic and transcriptional regulation of Bim in effector and memory CD8+ T cells; (iii) identification of molecular mechanisms controlling the accrual of CD4+ FoxP3+ regulatory T cells (and immunosuppressive function) in aging humans; (iv) mechanisms that regulate T cell homeostasis and function during sepsis. The long-term goal of the lab is to uncover novel therapeutic targets that can be used to promote T cell survival in some instances (e.g. vaccines, sepsis) and enhance T cell apoptosis in other instances (e.g. autoimmunity, lymphoid neoplasia).

Alex B. Lentsch, PhD Professor, Department of Surgery

Our laboratory studies molecular and cellular mechanisms of local and systemic inflammation induced by organ ischemia/reperfusion. Our work in this regard has evolved over the past 20 years, during which we have made several seminal contributions towards our understanding of the induction, propagation, and resolution of the acute inflammatory response to hepatic ischemia/reperfusion.  We are currently investigating the divergent roles of CXC chemokines in regulating the recovery and regeneration of damaged liver parenchyma after ischemic insult.  Most recently we have found that hepatocytes release exosomes that have proliferative effects during the process of tissue repair.  Moreover, the release of these exosomes is regulated by the CXC chemokine receptors, CXCR1 and CXCR2, in a manner completely independent from their known function as chemoattractant receptors.  I have also been intimately involved in other trauma-related research labs related to this training program in order to help provide our trainees the best research experience possible.

Amy T. Makley, MD Associate Professor, Department of Surgery

Our research focuses on understanding the roles of sphingosine-1-phosphate (S1P) and its receptor, S1P receptor 1 (S1PR1) in endothelial barrier function after massive transfusion for hemorrhage.  We have identified a loss of endothelial barrier function as a contributor to acute lung injury resulting from hemorrhage and resuscitation and preliminary evidence from our laboratory shows that the transfusion of aged pRBCs causes endothelial cell dysfunction in association with alterations in the S1P / S1PR1 signaling pathway.  The goals of our research are to determine the mechanisms by which the S1P / S1PR1 system regulates endothelial cell function and integrity, and elucidate the manner in which this system is altered by exposure to pRBCs following transfusion for hemorrhagic shock. To achieve our goals, we have established models of polytrauma and hemorrhagic shock in simulated and in vitro models to study endothelial cell barrier function.

Timothy A. Pritts, MD, PhD Professor, Department of Surgery

Our laboratory studies the impact of different resuscitation strategies for hemorrhagic shock. We have found that the ideal resuscitation fluid is a one to one ratio of packed red blood cells to fresh frozen plasma.  This work has influenced resuscitation strategies for massive transfusion at our trauma center and in the United States military. Some of our most recent efforts have examined the red blood cell storage lesion in packed red blood cells.  This lesion is a series of biochemical and physical changes in erythrocytes that leads to degradation of the quality of the red blood cell unit and harm to the recipient.  Our goal is to maximize the quality of erythrocytes transfused during resuscitation.  Additional work has focused on the special needs of the injured warfighter.  Through our partnership with the US military, we have worked together to advance our understanding of how to provide optimal care in austere and challenging environments, especially in the far-forward critical care transport setting.  Aspects of this work include the effect of aged, as compared to fresh, blood components as well as hypotensive resuscitative strategies on the host response to hemorrhagic shock.

Basilia Zingarelli, MD, PhD Professor, Department of Pediatrics, Critical Care Medicine, CCHMC

Our laboratory is focused on the investigation of the pathophysiologic mechanisms of sepsis, trauma and hemorrhagic shock, which are leading causes of morbidity and mortality in intensive care units. Ongoing projects are primarily funded by two R01 grants from the National Institutes of Health. Dr. Zingarelli has identified putative anti-inflammatory nuclear receptors, the peroxisome proliferator activated receptors (PPARγ, PPARα and PPARδ ), and liver X receptors (LXRs), which regulate gene transcription of several cytotoxic modulators and may be important defense factors. Recent research efforts also focus on understanding the role of aging on the clinical course of infections, severe hemorrhage and trauma. The Zingarelli laboratory is also investigating the role of the PPARγ co-activator-1α (PGC-1α) and the AMP activated kinase (AMPK) in a variety of metabolic processes with particular interest on the molecular mechanisms of autophagy, a process that allows the cell to dispose dysfunctional organelles, and mitochondrial biogenesis, a process that allows the cell to restore energy homeostasis. The laboratory employs a multidisciplinary approach combining in vivo and in vitro experimental models in genetically modified cell lines. These models are also utilized as a translational research platform to screen novel pharmacological compounds that can modulate the molecular mechanisms of organ function. The goal is to identify specific therapeutic interventions for pediatric, adult and elderly patients.

Current Trainees

M. Ryan Baucom, MD General Surgery Resident

Dr. Baucom entered the Goodman lab in July 2020. He is investigating whether the addition of hemorrhagic shock to TBI in a murine polytrauma model would affect p-tau expression and if the benefit of propranolol observed in non-trauma models would also be observed in the setting of trauma. His research is to support the hypothesis that the addition of hemorrhagic shock to TBI would increase posttraumatic p-tau expression and that the administration of propranolol would improve outcomes in a TBI-only trauma model as well as in a polytrauma model.

Adam Price, MD General Surgery Resident

Dr. Price entered the Goodman lab in July of 2022. He is studying the ways in which traumatic brain injury and hemodynamic shock interact with endothelial cell function to cause traumatic endotheliopathy. Dr. Price is utilizing cell culture, murine, and porcine models to investigate various in vitro and in vivo components to the endotheliopathy phenomenon.

Stephanie Sisak, MD General Surgery Resident

Dr. Sisak, under the mentorship of Dr. Pritts, is focusing her science on receptors for advanced glycation end products. Isolating the receptor for advanced glycation end products (RAGE) in mouse lung epithelial cells will begin her research regarding the RAGE-AGE axis. This investigation will attempt to define different factors that affect RAGE expression, how RAGE influences the inflammatory response, important ligands for RAGE in blood and tissue, and RAGE’s role in the red blood cell storage lesion. Specific projects will further examine the RAGE-AGE axis in both tissues and serum in a mouse model to extrapolate RAGE’s role in human blood and eventually in a clinical setting, particularly in how it relates to the specific population of trauma patients.

Application Process

Appointments begin on July 1 of each year. Interested applicants should submit a current CV and three letters of recommendation, no later than November 1 of the prior year, and send to the T32 program administrator below.

Betsy (Elizabeth) Rodarte Boiman, Program Director
Division of Research, Department of Surgery
University of Cincinnati
231 Albert Sabin Way, ML 0558
Cincinnati, OH 45267-0558
Elizabeth.Boiman@uc.edu
513-558-8674