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Robert S. B. Clark, MD

Vice Chair, Critical Care Medicine
Endowed Chair in Pediatric Critical Care Medicine
Director, Brain Care Institute
Associate Director, Safar Center for Resuscitation Research
Secondary appointments: Pediatrics, Clinical Translational Science Institute

 

412.692.7260
Admin Assistant: Janet Santucci
412.692.7260

Dr. Clark is Chief of the Division of Pediatric Critical Care Medicine. He provides clinical service for both the general and pediatric neurocritical care services. Broadly speaking, his current research interests include mechanisms of cell death and neurological dysfunction after traumatic and ischemic brain injury, particularly in the developing brain. Laboratory efforts encompass in vitro and in vivo models of brain trauma and ischemia, and translational studies in patients suffering from these injuries. He also has a strong interest in pediatric neurocritical care, and established the first primary pediatric neurocritical care service in the world along with Dr. Michael Bell whom he recruited to serve as Director. He has established an infrastructure for the successful training of young investigators, and have served as the primary research mentor for over 25 clinical fellows, post-doctoral fellows, graduate students, and or medical students. He has been Principal Investigator on 9 NIH grants since 1996, served as primary sponsor for three K08 and two K12 awardees, served as Co-PI on the T32 grant, “Training in Pediatric Neurointensive Care and Resuscitation Research,” for over 15 years, and has served on >80 NIH study sections since 2001. He has over 270 publications including over 170 peer-reviewed research manuscripts including publications in the ACS Chemical Biology, FASEB Journal, Journal of Biological Chemistry, and Journal of Neuroscience. In a recent report by Thomas Reuters Web of Science’s SCIENCEWATCH he was listed as one of the top 25 most prolific authors of papers on traumatic brain injury in the world from 2001-2014. His publications have been highlighted in Science, Nature, Scientific American, Science & Vie (Paris), and The Wall Street Journal.

 

Education and Training

Degree

Year

Field

Utah State University, Logan, UT

B.S.

1985

Engineering, Biology

Plymouth Polytechnic, Plymouth, England

Study Abroad

1983-1984

Biology

Medical College of Wisconsin, Milwaukee, WI

M.D.

1989

Medicine

University of Utah, Salt Lake City, UT

Resident

1992

Pediatrics

Children’s Hospital of Pittsburgh, Pittsburgh, PA

Fellow

1995

Critical Care Medicine

 

Other Experience and Professional Memberships

2000-2003, Program Committee, Society of Critical Care Medicine

2001-04 Charter Member NINDS Clinical Neuroscience and Disease study section

2001-present, Editorial Board, Pediatric Critical Care Medicine

2003-2013, Editorial Board, Journal of Neurotrauma

2003-present, Society for Pediatric Research

2004-05, Program Committee, National Neurotrauma Society

2005-09, Regular Member NINDS Developmental Brain Disorders study section

2008, Secretary/Treasurer National Neurotrauma Society

2007-present, AHA/NRCPR Pediatric Research Task Force member

2008-10, Chair Pediatric Critical Care Fellowship Committee, Society of Critical Care Medicine

2011, Vice President, National Neurotrauma Society

2009-18, Brain Disorders and Related Neuroscience F01 Fellowship Awards study section

Honors

1985                Jack P. and Bonnie F. Parsons Scholar

1994                Fellowship Award, American Heart Association

1995                Society of Critical Care Medicine Annual Scientific Award

1996                Fellow AAP

1996-1997       NIH Child Health Research Center Pediatrician/Scientist Development Award

1996-2001       NIH Mentored Clinical Scientist Development Award

1997                Children’s Hospital of Pittsburgh Michael E. Miller Young Investigator Award

1997                Society of Critical Care Medicine Young Investigator Award

1998                Society of Critical Care Medicine Neuroscience Award

2005                Al McGuire Lecturer, Children’s Hospital of Wisconsin

2009                Society of Critical Care Medicine Presidential Citation

2016                Fellow SCCM

 

Trainee Awards (serving as Primary Mentor)

2000    Neal Seidberg, MD                 Society of Critical Care Medicine Annual Scientific Award

2000    Margaret Satchell, MD           Society of Critical Care Medicine Annual Scientific Award

2000    Margaret Satchell, MD           Neurotrauma Society Murray Goldstein Award

2001    Margaret Satchell, MD           Society of Critical Care Medicine Annual Scientific Award

2003    Yichen Lai, MD                        Society of Critical Care Medicine Educational Scholarship

2005    Ericka Fink, MD                       AHA PA/DE Affiliate Fellow’s Research Day Top Prize

2005    Ericka Fink, MD                       Nancy Caroline Fellow for Resuscitation Research

2006    Yichen Lai, MD                        Society of Critical Care Medicine Educational Scholarship

2006    Yichen Lai, MD                        Nancy Caroline Fellow for Resuscitation Research

2007    Mioara Manole, MD               AHA PA/DE Affiliate Fellow’s Research Day Second Prize

2007    Mioara Manole, MD               Nancy Caroline Fellow for Resuscitation Research

2007    Craig Smith, MD                     Society of Critical Care Medicine Annual Scientific Award

2007    Ajit Sarnaik, MD                      Society of Critical Care Medicine Educational Scholarship

2008    Michael Shoykhet, MD           Children’s Hospital Advanced Research Fellowship Award

2009    Michael Shoykhet, MD           Pediatric Academic Societies Young Investigator’s Travel Award

2010    Michael Shoykhet, MD           Department of Critical Care Medicine McGrevin Post-Graduate Award

2010    Alicia Au, MD                          Society of Critical Care Medicine Neurology Specialty Award

2010    Alicia Au, MD                          Safar Symposium Oral Abstract Presentation Award

2011    Alicia Au, MD                          Department of Critical Care Medicine McGrevin Post-Graduate Award

2011    Alicia Au, MD                          Nancy Caroline Fellow for Resuscitation Research

2013    Anthony Willyerd                    Society of Critical Care Medicine In-Training Travel Award

2014    Alicia Au, MD                          Society of Critical Care Medicine Young Investigator Award

2014    Dennis Simon, MD                  Society of Critical Care Medicine In-Training Award

2015    Dennis Simon, MD                  Nancy Caroline Fellow for Resuscitation Research

2016    Dennis Simon, MD                   Children’s Trust Fund First Prize

2017    Christopher Horvat, MD           Nancy Caroline Fellow for Resuscitation Research

2018    Christopher Horvat, MD           Children’s Trust Fund First Prize

   

Contribution to Science

NCBI My Bibliography, September 7, 2018 (235 citations): http://www.ncbi.nlm.nih.gov/sites/myncbi/1RMAyNx1337Al/bibliography/45841584/public/?sort=date&direction=descending

1. Identification of mitochondrial poly(ADP-ribose) polymerase (PARP) as a direct mediator of cell death. This work was supported by an NIH program project grant awarded to the U. of Pittsburgh Brain Trauma Research Center (P.D. Ed Dixon). My project, “PARP Activation after Head Injury” used in vitro, in vivo, and clinical paradigms to tease out the role of PARP after TBI. We were the first to report nuclear translocation of apoptosis inducing factor (AIF) after acute brain injury in vivo, and that AIF-mediated cell death is regulated by mitochondrial PARP1 in neurons (1a). Our studies demonstrated that PARP is present and can be activated in multiple subcellular compartments, including mitochondria, under conditions of excitotoxicity and nitrosative stress and that electron transport chain proteins are post-translationally modified by PARP contributing to mitochondrial dysfunction and energy failure (1b). This represented a paradigm shift in the traditional view that nuclear PARP activation signaled mitochondrial cell death events. In keeping with the translational theme of my research, we developed an assay to quantify PARP activation in human tissues such as cerebrospinal fluid (CSF) (1c), and evaluated the impact of PARP single nucleotide polymorphisms in adults after severe TBI (1d).

Mitochondrially Targeted PARP Inhibitor, and Uses Thereof. Inventors: Hulya Bayir, Robert Clark, Tanja Kranz, Peter Wipf. United States Provisional Patent Application No. 62/407,639, filed October 13, 2016. International Patent Application PCT/US2017/056503, filed October 13, 2017

1a. Du L, Zhang X, Han YY, Burke NA, Kochanek PM, Watkins SC, Graham SH, Carcillo JA, Szabo C, Clark RS: Intra-mitochondrial poly-ADP-ribosylation contributes to NAD+ depletion and cell death induced by oxidative stress. J Biol Chem 2003;278:18426-18433. PMID: 12626504

1b. Lai Y, Chen Y, Watkins SC, Nathaniel PD, Guo F, Kochanek PM, Jenkins LW, Szabo C, Clark RS. Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury. J Neurochem 2008;104:1700-1711. PMID: 17996029

1c. Fink EL, Lai Y, Zhang X, Janesko-Feldman K, Adelson PD, Szabó C, Berger RP, Sarnaik AA, Kochanek PM, Clark RS. Quantification of poly(ADP-ribose)-modified proteins in cerebrospinal fluid from infants and children after traumatic brain injury. J Cereb Blood Flow Metab 2008;28:1523-1529. PMC2560585

1d. Sarnaik AA, Conley YP, Okonkwo DO, *Barr TL, Fink EL, Szabo C, Kochanek PM, Clark RS. Influence of PARP-1 polymorphisms in patients after traumatic brain injury. J Neurotrauma 2010;27:465-471. PMC2867630

 

2. Advancing the field of pediatric neurocritical care. I have a strong interest in pediatric neurocritical care, and established the first primary pediatric neurocritical care service in the world upon recruitment of Dr. Michael Bell. While first-rate clinical service is the priority of the neurocritical care service, it is also academically oriented and provides opportunities for clinical research-minded trainees. Recently published clinical studies reporting development of the first electronic medical record-triggered early warning system for deterioration of hospitalized patients (2a), recently highlighted in The Wall Street Journal (L. Landro, May 25, 2015, Hospitals-find-new-ways-to-monitor-patients); serum biomarkers for detection of unsuspected neurological morbidity (2b); and a foundation for precision-based sedation-analgesia strategies in critically ill children (2c).

2a. Da Silva YS, Hamilton MF, Horvat C, Fink EL, Palmer F, Nowalk AJ, Winger DS, Clark RS. Evaluation of electronic medical record vital sign data versus a commercially available acuity score in predicting need for critical intervention at a tertiary children’s hospital. Pediatr Crit Care Med 2015;16:644-651. PMID: 25901545

2b. Au AK, Bell MJ, Fink EL, Aneja RK, Kochanek PM, Clark RS. Brain-specific serum biomarkers predict neurological morbidity in diagnostically diverse pediatric intensive care unit patients. Neuro Crit Care 2018;28:26-34. PMID: 28612133

2c. Horvat CM, Au AK, Conley YP, Kochanek PM, Li L, Poloyac SL, Empey PE, Clark RS. ABCB1 genotype is associated with fentanyl requirements in critically ill children. Pediatr Res 2017;82:29-35. PMID: 28388599

2d. Horvat CM, Ismail HM, Au AK, Garibaldi L, Siripong N, Kantawala S, Aneja RK, Hupp DS, Kochanek PM, Clark RS. Presenting predictors and temporal trends of treatment-related outcomes in diabetic ketoacidosis. Pediatr Diabetes in press, 2018. PMID: 29573523

 

3. The discovery of innate sex-dependent susceptibility to neurotoxicity and proclivity toward cell death pathways, independent of circulating sex steroids. The provocative finding that girls after severe TBI had higher CSF levels of the apoptotic biomarker cytochrome c (3a), led to a “bedside to bench” approach where neurons isolated from male and female rodents were evaluated for their response to cell death stimuli and relevant therapies. This work, published in the Journal of Biological Chemistry (3b) was featured in Science (Mars-and-Venus, R. J. Davenport), Nature (Suffocating-Cells-Show-Sex-Difference, M. Hopkin,), and recognized in the 2014 NIH mandate to balance sex in cell and animal experiments (J. A. Clayton, F. S. Collins, NIH-to-balance-sex-in-cell-and-animal-studies). Sex-dependent differences in response to starvation in neurons in culture were also discovered, where neurons from males utilize protein sources for fuel and undergo autophagy, whereas neurons from females utilize fat sources for fuel and form lipid droplets, surviving longer than neurons from males (3c). To evaluate sex-dependent, sex steroid-independent, responses in vivo, the R01 entitled “Gender-Specific Treatment of Pediatric Cardiac Arrest was funded after development of a novel model of pediatric asphyxial arrest in rodents. Consistent with in vitro studies, a sex-dependent response to antioxidant therapies after cardiac arrest was observed (3d).

3a. Satchell MA, Lai Y, Kochanek PM, Wisneiwski SR, Fink EL, Seidberg NA, Berger RP, DeKosky ST, Adelson PD, Clark RS. Cytochrome c, a biomarker of apoptosis, is increased in cerebrospinal fluid from infants with inflicted brain injury from child abuse. J Cereb Blood Flow Metab 2005;25:919-927. PMID: 15744250

3b. Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, Graham SH, Clark RS. Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem 2004;279:38563-38570. PMID: 15234982

3c. Du L, Hickey RW, Bayir H, Watkins SC, Tyurin VA, Guo F, Kochanek PM, Jenkins LW, Ren J, Gibson G, Chu CT, Kagan VE, Clark RS. Starving neurons show sex difference in autophagy. J Biol Chem 2009;284:2383-2396. PMC2629091

3d. Manole MD, Kochanek PM, Foley LM, Hitchens TK, Bayir H, Alexander H, Garman R, Ma L, Hsia CJC, Ho C, Clark RS. Polynitroxyl albumin and albumin therapy after pediatric cardiac arrest: Effects on cerebral blood flow and neurological outcome. J Cereb Blood Flow Metab 2012;32:560-569. PMC3293121

 

4. Uncovering the role of drug transporters in TBI. Brain bioavailability of drugs and xenobiotics is tightly regulated by drug transporters at the blood-brain and blood-CSF barriers (BBB and BCSFB). These include the multidrug resistance and resistance-associated protein ATP-binding cassette (ABC) transporters (e.g. P-glycoprotein/MDR1/ABCB1, MRP1/ABCC1) and organic acid transporters and transporting peptides (OAT and OATP). Despite their importance to pharmacokinetics and brain bioavailability of medicines used for standard care and potential neuroprotection, little is known regarding the role of these drug transporters in TBI, nor the response of these drug transporters to injury. As such, an R01 entitled “Overcoming Membrane Transporters to Improve CNS Drug Therapy” was funded in 2009 to address this scientific and clinical gap, that included in vitro and in vivo models, and a Phase I clinical trial to test the antioxidant N-acetylcysteine (NAC) in combination with the transporter inhibitor probenecid (4a, b; ClinicalTrials.gov ID: NCT01322009). These studies leveraged existing pharmacologic agents that increase exposure of neuroprotective agents in brains vulnerable after injury. We also reported the influence of genetic polymorphisms in ABC transporters after TBI (4c) and the impact of TBI on ABC transporters in humans, evaluated the direct effect of the combination of probenecid and NAC on neurons after mechanical stretch injury in vitro, and discovered that NAC is a substrate for OAT1 and 3, and that brain exposure can be increased with co-administration of probenecid (4d).

4a. Clark RS, Empey PE, Bayir H, Rosario BL, Poloyac SM, Kochanek PM, Nolin TD, Au AK, Horvat CM, Wisniewski SR, Bell MJ. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children. PLOS One 2017;12(7):e0180280. PMID: 28686657

4b. Hagos FT, Empey PE, Wang P, Ma X, Poloyac SM, Bayır H, Kochanek PM, Bell MJ, Clark RS. Exploratory application of neuropharmacometabolomics in severe childhood traumatic brain injury. Crit Care Med in press, 2018. PMID: 29742587

4c. Cousar JL, Conley YP, Willyerd FA, Sarnaik AA, Puccio AM, Empey PE, Kochanek PM, Bell MJ, Okonkwo DO, Clark RS. Influence of ATP-binding cassette polymorphisms on neurological outcome after traumatic brain injury. Neurocrit Care 2013;19:192-198. PMC4332629

4d. Hagos FT, Daood MJ, Ocque JA, Nolan TD, Bayır H, Poloyac SM, Kochanek PM, Clark RS, Empey PE. Probenecid increases plasma and brain exposure of N-acetylcysteine through a mechanism involving inhibition of OAT1 and OAT3 transporters. Xenobiotica 2017;47:346-353. PMID: 27278858

 

5. Translating mechanisms of cell death after TBI from bench to bedside. My early work focused on molecular mechanisms of cell death after TBI, supported by an NIH K08 Award entitled, “Role of Endogenous Neuroprotective Genes after Traumatic Brain Injury” (Sponsor: Steve Graham). Continuation of this work was supported by an R01 entitled, “Caspase-Mediated Neuronal Death after Head Injury”, to support investigation in both experimental models and in humans, a translational approach that was considered “ahead of its time” by Study Section Reviewers; then competitively renewed in 2003 and 2009 as “Divergent Pathways of Cell Death after Brain Injury.” This work led to the seminal findings that the anti-apoptotic gene bcl-2 is induced in surviving neurons after TBI in rats (5a) and adult and pediatric patients (5b and 5c), and multiple other publications demonstrating a role for caspases (5b and 5d), stress proteins, cell death receptors, and other bcl-2 family members after TBI.

5a. Clark RS, Chen J, Watkins SC, Kochanek PM, Chen M, Loeffert JE, Stetler RA, Graham SH. Apoptosis suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci 1997;17:9172-9182. PMID: 9364064

5b. Clark RS, Kochanek PM, Chen M, Watkins SC, Marion DW, Hamilton RL, Chen J, Loeffert JE, Graham SH. Increase in Bcl-2 and cleavage of Caspase-1 and Caspase-3 in human brain after head injury. FASEB J 1999;13:813-821. PMID: 10224225

5c. Clark RS, Kochanek PM, Adelson PD, Bell MJ, Carcillo JA, Chen M, Wisniewski SR, Janesko K, Whalen MJ, Graham SH. Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed-cell death in infants and children following severe traumatic brain injury. J Pediatr 2000;137:197-204. PMID: 10931412

5d. Zhang X, Graham SH, Kochanek PM, Marion DW, Nathaniel PD, Watkins SC, Clark RS. Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J 2003;17:1367-1369. PMID: 12738800

 

Ongoing Research Support

NINDS R01 NS084604           Clark/Bayir      (MPI)       3/15/14-12/31/18

Mitochondria-targeted Redox Therapy for Cerebral Ischemia in the Developing Brain

Design, develop and test novel mitochondria-targeting therapeutics toward improving neurological outcome after pediatric cardiac arrest.

Role: Principal Investigator (Contact PI)

NINDS R21NS098057            Travis Jackson (PI)       2/1/17-1/31/19      

FGF21 Activates RBM3 and is a Novel Drug to Revolutionize Temperature Management

Test the hypothesis that fibroblast growth factor 21 activates cold-shock protein RNA binding motif 3 as a novel means of neuroprotection after a brain injury.

Role: Co-Investigator

NINDS R01 NS102195           Steven Graham (PI)       7/1/17-6/30/22

Role of UCHL1 in Axonal Injury and Recovery after TBI

Role: Co-Investigator

NINDS K23 NS104133           Alicia Au (PI)            7/1/18-6/30/23
Mixed Graphical Models for the Prediction of Neurological Morbidity in the PICU

Role: Primary Sponsor

NINDS 1R01 NS096714   Ericka Fink (PI)            6/30/16-5/31/21

Development of Serum, Imaging, and Clinical Biomarker Driven Models to Direct Clinical Management after Pediatric Cardiac Arrest

Role: Co-Investigator

NINDS 1U54 NS100064         Paul Vespa (PI), Sub-award, U. of Southern California       1/1/17-11/30/19

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx)

Role: Clinical Site PI

NINDS 1R01 NS096053  Bradley Kurowski (PI), Sub-award, Cincinnati Children’s Hosp   8/1/16-4/30/21

Genetic and Environmental Influences on Recovery of Severe Brain Injury

Role: Clinical Site PI

NINDS 1R01 NS092870         Peter Ferrazzano (PI), Sub-award, U. of Wisconsin       4/1/16-3/31/20

MRI Markers of Functional Outcome after Severe Pediatric TBI

Role: Clinical Site PI

NICHD T32 HD40686             Patrick Kochanek (PI)      7/1/06-6/30/20

Training in Pediatric Neurointensive Care and Resuscitation Research

Develop Clinician Scientists in Pediatric Neurointensive Care research.

Role: Co-Principal Investigator