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Mentors and Ongoing Projects

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Aneja | Bayır | Dezfullian | Kahn | Kaynar

Kellum | Kochanek | Murugan | Pinsky

 

  • Raj Aneja
    • Dr. Aneja’s research entails understanding the regulation of the heat shock response by a nuclear protein called Poly (ADP) ribose polymerase (PARP). Recent studies indicate that PARP-1 also acts as a co-transcription factor for many cellular proteins. Dr. Aneja is also examining its impact on lipopolysaccharide mediated High Mobility Group Box 1 (HMGB-1) protein secretion. HMGB-1 is a DNA binding protein with cytokine like properties and is thought to be a key mediator of sepsis. Dr. Aneja’s clinical research interests include the use of plasma exchange in multi-organ failure associated with sepsis.
    • Major projects:
      • Regulation of LPS-Mediated HMGB1 Release by Poly (ADP-Ribose) Polymerase-1
        This research will define the role of PARP-1 in the modulation of Lipopolysaccharide (LPS)-medicated HMGB1 transcription, post-translational modification and secretion.
      • Role of Danger Associated Molecular Patterns in Traumatic Brain Injury and Sepsis
        Working with Drs. Kochanek, Bayır, and Bell, this project will examine the role of danger associated molecular patterns in traumatic brain injury and sepsis.
  • Hülya Bayır
    • Dr. Hülya Bayır’s research continues to focus on the primary themes of mitochondrial injury and oxidative stress. She has organized a multidisciplinary team of investigators to study novel approaches to the treatment of mitochondrial dysfunction by targeting oxidative stress. Her laboratory integrates the work of clinical and basic science researchers. Her group has recent publications in Nature Neuroscience, Nature Cell Biology, and Nature Chemistry among others.
    • Major projects:
      • Oxidative Lipidomics in Pediatric Traumatic Brain Injury
        Funded by: National Institute of Neurological Disorders and Stroke (NINDS). 2R01NS061817, Role: PI; Co-Is: P. Kochanek; D. Stoyanovsky (EOH/GSPH); V. Kagan (EOH/GSPH). This project employs the newly developing technology of oxidative lipidomics to provide important mechanistic information on the role of oxidized phospholipids in neuronal apoptosis after pediatric traumatic brain injury.
      • University of Pittsburgh CMCR Project 4, Mitochondria-targeted small molecule stabilizers and mimics of MnSOD as radiomitigators
        Funded by: National Institute of Allergy and Infectious Diseases (NIAID), 2U19AI068021, Role: PI; Co-Is: J Peterson (EOH/GSPH), L Pearce (EOH/GSPH), J Klein-Seetharaman (Structural Biology). The central hypothesis of this project is that small molecules that lead to stabilization of MnSOD catalytic activity and/or act as mitochondria targeted SOD mimics represent new types of radiomitigators.
      • Mapping Lipid Oxidation in Traumatic Brain Injury by Mass Spectrometric Imaging
        Funded by: National Institute of Neurological Disorders and Stroke (NINDS). 1R01NS076511, Role: PI; Co-PI: VE Kagan; Co-Is: P Kochanek, A. Amoscato (EOH/GSPH), A. Kline (PM&R), S. Watkins (Cell Biology). The goal of this application is to develop and apply a new technology – imaging mass spectrometry (IMS) – for spatial and temporal mapping of diverse molecular species of phospholipids and their oxidation products and superimposing them onto neuropathology of the injured brain.
      • Mitochondria-Targeted Redox Therapy for Cerebral Ischemia in the Developing Brain
        Funded by: National Institute of Neurological Disorders and Stroke (NINDS). 1R01NS084604, Role: PI; Co-PI: RSB Clark; Co-Is: P Kochanek, P. Wipf (Chemistry), M Manole (Pediatrics), D. Stoyanovsky (EOH/GSPH), A. Kline (PM&R). The aim of this research is to synthesize and develop novel mitochondria-targeting therapeutics, toward meaningfully improving neurological outcome and quality of life in infants and children suffering from cerebral hypoxia-ischemia.
      • Oxygenated Species Of Cardiolipins As Biomarkers Of Mitochondrial Dysfunction, Role: Co-Investigator
        Funded by: National Institute of Environmental Health (NIEHS). R01ES020693. Role: Co-I; PI: YY Tyurina and VE Kagan. The central hypothesis of this project is that exposure to rotenone, a pesticide, causes time- and dose-dependent selective oxidation of cardiolipin and accumulation of its oxidized molecular species associated with mitochondrial dysfunction through enzymatic reactions triggered early in apoptosis.
      • Overcoming Membrane Transporters to Improve CNS Drug Therapy
        Funded by: National Institute of Neurologic Diseases and Stroke R01NS069247, Role: Co-I; PI: Robert Clark, MD; other Co-Is: Patrick Kochanek, MD; Michael Bell, MD. There is a sense of urgency to move forward with pharmacological therapies that improve outcome after brain injury. This project tests combinational strategies that overcome membrane transport barriers to synergistically improve bioavailability and efficacy of both clinically used and novel therapies after traumatic brain injury. We aim to define the capacity of the combination of probenecid and N-acetylcysteine (NAC) to synergistically reduce oxidative stress and improve neurological outcome in experimental models, and to define the capacity of the combination of probenecid and NAC to safely and synergistically reduce oxidative stress in children (Phase I/II Pro-NAC trial), after traumatic brain injury.
      • Cardiopulmonary bypass (CPB) and organ dysfunction: association with hemolysis and cell-free hemoglobin
        Funded by: Vascular Medicine Institute, University of Pittsburgh. Role: Mentor; PI: N. Kim-Campbell. This proposal evaluates association of cell free hemoglobin with CPB- induced organ dysfunction in children and investigates mechanisms of organ dysfunction and potential therapies in an experimental model of CPB.
  • Cameron Dezfullian
    • Dr. Cameron Dezfulian is interested in ways of reducing cerebral and cardiac injury resulting from cardiac arrest. In the lab, he has developed mouse and rat models of cardiac arrest to study the effects of nitrite, an ischemic reservoir for nitric oxide and potent S-nitrosating agent, in achieving this organ protection. Active areas of investigation surround signaling related to S-nitrosation in mitochondria and survival pathways. New lab and clinical projects examining the phenotypes of heterogeneous forms of cardiac arrest are now underway. Dr. Dezfulian is working to translate promising findings from bench to bedside and has begun a phase I study of nitrite in cardiac arrest survivors. Additional translational projects being done in collaboration with other Pitt investigators include: 1) examining the role of cardiolipin as a tissue specific injury marker and signaling molecule in human cardiac arrest survivors, 2) role of endothelial function, nitrite, mitochondrial ROS and DAMPs in signaling protection after ischemic preconditioning and 3) the role of various NOS isoforms and tissue sources of NO in the development of congenital heart disease and the outcomes of corrective surgery. Clinically, he is interested in aspects of post-resuscitation care which may affect these organ injuries. Current projects examine the role of hemodynamic support, multimodality neurological monitoring in mitigating cerebral and cardiac injury as well as a methodology to predict the need for coronary intervention in atypical cardiac arrest presentations. Dr. Dezfulian is a member of the Safar Center for Resuscitation Research, the Vascular Medicine Institute and the UPMC post-cardiac arrest service and in charge of cardiac arrest post-resuscitation quality improvement at UPMC Mercy.
    • Major projects:
      • Nitrate Based Neuroprotection After Cardiac Arrest
        Dr. Dezfulian is an adult and pediatric critical care physician acutely aware of the paucity of post-resuscitation therapies for the cardiac arrest survivors he cares for. This career development award supplements his research background with senior mentorship and lab-based and didactic training in neurosciences and redox signaling. The research plan is based on preliminary observations which support the hypothesis that nitrite-mediated neuroprotection after cardiac arrest occurs through nitric oxide (NO) and S-nitrosothiol (S-NO)-based signaling that prevents subsequent signaled neuronal death and mitochondrial dysfunction. This hypothesis will be tested along three aims: (1) to define the optimal nitrite dose and timing and quantify the relative contributions of NO- and S-NO based signaling in neuroprotection, (2) to test whether nitrite-mediated neuroprotection results from nitrosylation of critical cell survival signals, and (3) to test whether nitrite-mediated NO and S-NO production effects mitochondrial function and prevents apoptosis.
  • Jeremy Kahn
    • Dr. Kahn’s research program focuses on the organization, management, and financing of critical care services in the United States. Specific areas of interest include ICU workforce and staffing, quality measurement, benchmarking, and regionalization of critical care. His work integrates approaches from the fields of epidemiology, health services research, health economics and organizational science to investigate novel strategies for increasing the quality and efficiency of critical care.
    • Major projects:
      • Contributors to Effective Critical Care Telemedicine (ConnECT)
        Telemedicine is a novel technology-based strategy to improve the quality of critical care, particularly in small, rural hospitals. However, many ICU telemedicine programs have failed to improve outcomes, leaving clinicians with little guidance about how and where to best apply this technology. Funded by the National Institutes of Health (R01HL120980), Dr. Kahn is using qualitative and quantitative research methods to understand the organizational factors that contribute to successful telemedicine programs and develop a “toolkit” to help hospitals effectively use telemedicine to improve the quality of critical care.
      • Determinants of Effective Long Term Acute Care (DELTA)
        Long-term acute care hospitals (LTACs) provide specialty inpatient care to patients recovering from severe acute illness. However, little is known about to organize and manage in order to optimize care for these high-risk, high-cost patients. Funded by the NIH (R01HL096651), Dr. Kahn using a mixed-methods approach to look with within LTACs to determine the factors associated with improved survival for patients with chronic critical illness.
      • Novel approaches to benchmarking hospitals on their critical care mortality
        The lack of robust performance measures for the care of critically ill patients is a major hindrance to ICU comparative effectiveness research, particularly research in how to optimally design regional systems of care. Funded by the NIH (R01HL126694), Dr. Kahn is using state-of-the-art statistical modeling approaches to develop and validate novel critical care performance measures that account for the complex trajectories of acutely ill patients through the health system, addressing a key barrier to progress in the fields of comparative effectiveness research and T3 translation.
      • Optimizing Utilization and Rural Emergency Access for Children (OUTREACH)
        Over 26.3 million US children visit an emergency department (ED) each year, comprising 22% of all ED visits. However, only 7% of US hospitals are fully equipped to deal with pediatric emergencies. In response to this problem, the Institute of Medicine recommended the adoption of “regionalized, accountable systems of pediatric emergency care.” Funded by the US Health Resources and Services Administration (H3AMC24076), Dr. Kahn’s research group is partnering with the Children’s Hospital of Pittsburgh of UPMC and 6 local community hospitals to develop, implement, and evaluate a regionalized system of pediatric emergency care in rural Western Pennsylvania.
  • Murat Kaynar
    • Dr. Murat Kaynar’s research continues to focus on the primary themes of sepsis, acute lung injury and ventilator-induced lung injury (VILI). He is studying matrix metalloproteinases (MMP) to elucidate their role in sepsis and VILI and subsequently aims to apply to the management of these diseases. He also added a Drosophila model of sepsis to his armamentarium to dissect the long-term outcome after sepsis. His work involves small animal models of the aforementioned diseases.
      Along the same line of long-term effects of acute inflammatory events, Dr. Kaynar is exploring the role of intra-operative mechanical ventilation in the operating room to outcomes in thoracic surgery patients. He is extracting data from anesthesia electronic medical records.
    • Major projects:
      • Neutrophil Collagenase in Sepsis and Ventilator Induced Lung Injury
        The primary goal of this career development award is to develop a better understanding of the mechanisms of sepsis leading to more effective therapies for patients.
      • Role of MMPs in Sepsis
        The project’s primary goals are to test the role of neutrophil specific MMPs in the pathogenesis of sepsis in established animal models. The main theme of Dr. Kaynar’s K08 is focusing on this theme.
      • MMP Polymorphisms in sepsis
        The project’s primary goal is to bridge the bench findings of animal models of sepsis to the available large data set of human sepsis established in our Department of Critical Care Medicine.
      • Long-term effects of mechanical ventilation in minimally invasive esophagectomy
        The project’s primary goal is to test the hypothesis that high intra-operative tidal volumes lead to increased 28 and 90 day mortality.
  • John Kellum
    • Dr. John Kellum’s research focuses on translational research and personalized medicine for critical illness. He has organized a multidisciplinary team of investigators to study novel approaches to the treatment of sepsis and to the understanding of the pathogenesis of and explore novel interventions for acute kidney injury. He directs the Center for Critical Care Nephrology which integrates the work of epidemiology and health service research with studies of basic mechanism of disease and new methods of treatment with a focus on fluid, electrolyte, acid-base and renal disorders in the critically ill and injured.
    • Major projects:
      • Protocolized Goal-directed Resuscitation of Septic Shock to Prevent Acute Kidney Injury (ProGReSS AKI)
        The incidence of acute kidney injury (AKI) is estimated at approximately 2000 per million of the population. This study will examine the effect of protocolized resuscitation on the development of AKI. It also seeks to explore mechanisms underlying the effect of the intervention and to evaluate markers of renal injury and repair in order to help select patients for future interventional trials.
      • Cell-cycle Arrest Biomarkers for Acute Kidney Injury (Sapphire-Topaz)
        This project is focused on the discovery and validation of markers of G1 cell-cycle arrest as diagnostics and therapeutic targets for Acute Kidney Injury. The project encompasses clinical trials, animal and in vitro studies.
      • Clinical Risk-Prediction for Acute Kidney Injury Based on Electronic Medical Record Data
        Acute Kidney Injury (AKI) affects nearly two-thirds of patients admitted to ICU and those developing this condition have twice the risk of death by 90-days and their ICU and hospital costs are double. Our project will identify patients at highest risk for AKI and for AKI progression. By comparing rates and outcomes for AKI across multiple centers we will also identify opportunities to improve care for these patients.
      • Novel Model-systems for Acute Kidney Injury
        Acute Kidney Injury (AKI) is a vexing clinical problem with no effective therapy. Model systems do not exist for the most common forms of AKI such as sepsis. We are developing novel model systems including rodent, zebra-fish, 3-demensional human primary cell culture and isolated perfused human kidney models for the study of diagnostics and therapeutics for AKI.
      • Hyperchloremic Acidosis in Critically Ill Patients and Outcomes of Fluid Resuscitation
        Currently recommended resuscitation paradigms involve a “crystalloid-first” approach, reserving colloids for patients that have already been exposed to large amounts of crystalloid and may also have had a delay in correcting their shock. Using our ICU database we are analyzing data from a large cohort of ICU patients (n = > 50,000) to determine which variables predict outcomes. From this analysis we will study the effects of fluid choice on short term outcomes (acidosis, acute kidney injury) and long term outcomes (permanent dialysis and mortality). The results of this study will provide important groundwork for the future development of novel resuscitation fluids, in addition to providing estimates of effect sizes and power required to execute future interventional studies using novel resuscitation fluids.
  • Patrick Kochanek
    • Dr. Kochanek’s research addresses studies in experimental and clinical traumatic brain injury (TBI) and cardiac arrest (CA). His work also encompasses pediatric and adult arenas. Areas of focus are development of novel therapies for TBI, novel approaches to TBI resuscitation, pediatric TBI and abusive head trauma, adenosine and purine, metabolism in TBI, blast TBI, novel therapeutic approaches to prevent brain injury after cardiac, arrest and resuscitation, and futuristic resuscitation strategies such as emergency Preservation and Resuscitation.
    • Major projects:
      • Operation Brain Trauma Therapy
        Dr. Kochanek is the head of multicenter pre-clinical drug screening consortium for the United States Army titled Operation Brain Trauma Therapy (OBTT). The consortium includes investigators at the University of Pittsburgh, The University of Miami (Miami project to cure paralysis), Walter Reed Army Institute of Research, the Virginia Commonwealth University, the University of Florida, Messina University in Sicily, and Banyan Biomarkers, LLC. OBTT is testing therapies across multiple TBI models and species to define a potent therapy for TBI for ultimate use in combat casualty care.
      • Operation Brain Trauma Therapy Extended Studies
        Based on the success of OBTT, the United States Army recently funded supplemental investigations by the OBTT consortium, to expand its drug testing and include higher risk drugs that may have the potential for high reward. The same investigative team as OBTT is involved supplemented by additional support in pharmacology/pharmacy.
      • Polynitroxylated pegylated hemoglobin for traumatic brain injury resuscitation (PNPH)
        Funded by NIH 1U44NS070324-01A1, Role: Site PI; PI: Carlton Hsia, PhD (SynZyme Technologies). In this project, Dr. Kochanek and his team at the Safar Center are collaborating with investigators at SynZyme technologies LLC, on the development of PNPH as an ultra-small volume resuscitation fluid in the setting of severe TBI plush hemorrhagic shock. In these studies, a unique mouse model is being used to study the potential efficacy of PNPH including studies needed to advance this agent to clinical testing.
      • 2',3'-cAMP in TBI
        Funded by NIH 1R01NS087978, Role: Dual PI with Edwin Jackson, PhD, Co-I: C. Edward Dixon, PhD, Travis Jackson, PhD. Drs. Kochanek and Jackson, using studies in cell culture and a mouse model of TBI, are elucidating which CNS cell types produce 2’,3’-cAMP, what kinds of injury trigger 2’,3’-cAMP production, how 2’,3’-cAMP is transported out of cells, how downstream AMPs are converted to adenosine, and if manipulating the 2’,3’-cAMP-adenosine pathway alters secondary damage after TBI. The overall hypothesis is that the “2’,3’-cAMP-adenosine pathway” is an endogenous cytoprotective mechanism after TBI.
  • Ragi Murugan
    • Dr. Raghavan Murugan’s research interests spans a number of domains in critical illness including acute kidney injury, sepsis, organ transplantation, and mechanisms of recovery from organ dysfunction.
    • Major projects:
      • A clinical trial of recombinant alkaline phosphatase infusion in sepsis-associated acute kidney injury (AKI)
        Sepsis is a leading cause of AKI and is associated with increased risk of death. Alkaline phosphatase is an endogenous enzyme present in many cells and organs that exerts detoxifying effects through dephosphorylation of endotoxins including extracellular adenosine triphosphate. There is increasing evidence that the protein plays a significant role in host defense and innate immunity, particularly against inflammatory reactions due to lipopolysaccharide (LPS) release. Dr. Murugan is a site investigator for this multicenter, randomized, double-blind, placebo-controlled, four-arm, parallel-group, proof of concept, and dose-finding adaptive phase 2a/2b study to investigate the safety, tolerability and efficacy and effect on quality of life of human recombinant alkaline phosphatase in the treatment of patients with sepsis-associated AKI.
      • A clinical trial of recombinant angiotensin II infusion in catecholamine-resistant hypotension
        Catecholamine-resistant hypotension is an often a fatal condition resulting from an underlying cause such as septic shock, trauma, or severe drug reactions. Approximately, 6-7% of patients will require excessive doses of vasopressors and will be deemed to be resistant. Angiotensin II is a hormone produced by the renin angiotensin aldosterone system that modifies blood pressure via regulation of vascular smooth muscle tone and extracellular fluid homeostasis. As a site investigator of this phase 3, placebo-controlled, randomized, double-blind, multi-center study, Dr. Murugan is investigating the role of angiotensin II infusion in patients with catecholamine-resistant hypotension.
      • Timing of renal replacement therapy in critically ill patients with AKI
        AKI requiring renal replacement therapy (RRT) is a common and devastating complication of critical illness. Such patients have an in-hospital mortality that consistently exceeds 50% with delays in RRT initiation implicated as a possible contributor. The objective of this multinational clinical trial is to examine whether early initiation of RRT is associated with lower mortality and improved renal recovery in 2,866 critically ill patients with severe AKI who do not have an urgent indication for RRT initiation at the time of screening but who have a reasonable likelihood of ultimately requiring RRT. Dr. Murugan serves as a site-investigator of this trial.
      • Fluid overload and outcomes in critically ill patients
        Fluid overload is common in critically ill patients and is associated poor outcomes. Using a large dataset of critically ill patients, Dr. Murugan’s research focuses on understanding the association between magnitude of fluid overload and recovery of organ function with a specific focus on renal recovery.
      • MOnIToR Post: Monitoring Organ donors to Improve Transplantation Results- a prospective observational study
        This project is aimed at improving transplantation outcomes by reversing acute organ dysfunction in the donor using protocolized resuscitation. Our efforts have culminated in a consortium of eight organ procurement organizations that are engaged in research to improve organ function by use of targeted resuscitation using functional hemodynamic monitoring. This observational study is investigating resuscitation practices after the completion of a large clinical trial.
  • Michael Pinsky
    • Dr. Michael Pinsky’s work spans various aspects of critical care medicine but centers on hemodynamic monitoring based on cardiopulmonary physiology, sepsis and acute organ dysfunction and focuses on using machine learning principles to diagnose and treat critical illness. Over the past 35 years, he has organized multidisciplinary teams of investigators to study novel approaches to the diagnosis of left and right ventricular dysfunction, circulatory shock, long-term outcome form critical illness, complexity modeling of critical illness and the use of complex modeling feedback to diagnose and treat critical illness in man.
      Dr. Pinsky’s Cardiopulmonary Research laboratory integrates the work of computation biology, health service research and minimally invasive hemodynamic monitoring to understand the basic mechanism of cardiovascular collapse and response to therapies in all forms of circulatory shock. Recent research foci have been on endothelial dysfunction, mitochondrial dysfunction and microcirculation imaging in trauma, sepsis and hemorrhagic shock in porcine models; pattern recognition of physiologic responses to defined stressors, and microcirculatory and mitochondrial injury and repair.
      Other Research Interests of Dr. Pinsky’s include the use of integrated monitoring systems to improve recognition of cardiorespiratory instability and highly invasive human models assessing both left and right ventricular dysfunction prior to left ventricular assist device insertion.
    • Major projects:
      • Complexity Modeling of Critical Illness
        Funding: Edwards LifeSciences, Role: PI; Co-Is: Gilles Clermont, Artur Dubrawski. This industry-sponsored partnership examines the dynamical signatures of stable and hypovolemic physiological states in porcine models of hemorrhage and acute endotoxemia and in human physiologic data streams from critically ill infants (Children’s Hospital) and UPMC Presbyterian with the goal of defining early markers of instability and definitive signatures of sepsis and hypovolemia so as to alert bedside care givers earlier and allow for therapy prior to the development of overt shock.
      • Predicting patient instability noninvasively for nursing care (PPINNC)
        Funding: NIH, NRI R01 NR013912-01, Role: PI; Co-PI: Marilyn Hravnak; Co-Is: Gilles Clermont, Artur Dubrawski. This study aims to mine the existing clinical database of one year’s continuous non-invasive vital sign data base from one step-down unit to create identification algorisms based on machine learning to identify earlier cardiorespiratory insufficiency, stability and vital sign artifact with a high degree of specificity.
      • Microvascular alterations in severe hemorrhagic shock
        Funding: NIH, NHLBI 5-K12 HL109068-03; Role: Mentor; PI: Hernando Gomez; Mentors: John A. Kellum, Brian Zuckerbraun. This study uses porcine and murine models of sepsis and circulatory shock to study the link between mitochondrial dysfunction and its microcirculatory changes asking which comes first or do both occur at the same time
      • Trans-Agency Research Consortium for Trauma-Induced Coagulopathy (TACTIC)
        Funding: NIH-DoD NHLBI 1 UM1 HL120877-01, Role: Co-I; Overall PI: Kenneth Mann, Project 9: “Trauma-induced endothelial injury and inflammation that results in coagulopathy and end-organ damage”; Co-Is: Brian Zuckerbraun, Hernando Gomez. This large program project grant focuses on the pathophysiologic mechanisms for trauma-induced coagulopathy. Our project is to examine the endothelial injury as measured by cell surface receptor expression, activation of coagulation cascades and microcirculatory changes.
      • Developing Goal-Directed Perfusion Therapy for Neurocardiac Injury in Sub-Arachnoid Hemorrhage
        Funding: NIH NHLBI 2-R01 HL074316-06–A1, Role: Co-I; PIs: Marilyn Hravnak, Robert Friedlander; Co-Is: Yuefang Chang, John Gorcsan, Paula Sherwood, Samuel Poloyac, Brian Jankowitz. This clinical observational trial measures the multiple cardiovascular changes associated with the initial sub-arachnoid hemorrhage injury asking the question: Does neurogenic cardiac injury occur during sub-arachnoid hemorrhage and to what extent is it minimized by neuroprotective therapies.