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Robert S. B. Clark, MD

Chief, Pediatric Critical Care Medicine

Tenured Professor of Critical Care Medicine

Secondary appointments: Pediatrics and Clinical and Translational Science

Associate Director, Safar Center for Resuscitation Research

412.692.5164
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 two K08 and two K12 awardees, served as Co-PI on the T32 grant, “Training in Pediatric Neurointensive Care and Resuscitation Research,” for the past 15 years, and has served on 62 NIH study sections since 2001. He has over 200 publications including over 140 peer-reviewed research manuscripts including publications in the 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

2009-15, Member 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

 

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

          

Contribution to Science

NCBI My Bibliography, June 15, 2015 (192 citations): http://www.ncbi.nlm.nih.gov/sites/myncbi/1RMAyNx1337Al/bibliography/45841584/public/?sort=date&direction=descending

 

1. Translating mechanisms of cell death after traumatic brain injury (TBI) from bench to bedside. Dr. Clark’s 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 funded in 1996 (Sponsor: Steven Graham). Continuation of this work was supported by an R01 entitled, Caspase-Mediated Neuronal Death after Head Injury, funded in 1999 to support investigation in both experimental models and in humans, a translational (bench to bedside) approach that was considered “ahead of its time” by Study Section Reviewers; then competitively renewed in 2003 and again in 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 traumatic brain injury in both rats (1a) and adult and pediatric patients (1b and 1c), and multiple other publications demonstrating a role for caspases (1b and 1d), stress proteins, cell death receptors, and other bcl-2 family members after TBI.

1a. Clark RSB, 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

1b. Clark RSB, 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

1c. Clark RSB, 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

1d. Zhang X, Graham SH, Kochanek PM, Marion DW, Nathaniel PD, Watkins SC, Clark RSB. Caspase-8 expression and proteolysis in human brain after severe head injury. FASEB J 2003;17:1367-1369. PMID: 12738800

 

2. 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 (funded for two cycles) awarded to the University of Pittsburgh Brain Trauma Research Center (P.D. Edward Dixon). Dr. Clark’s project, PARP Activation after Head Injury used in vitro, in vivo, and clinical paradigms to tease out the role of poly(ADP-ribose) polymerase after TBI. His laboratory was the first to report nuclear translocation of apoptosis inducing factor (AIF) after any type of acute brain injury, and that AIF-mediated cell death is regulated by mitochondrial PARP in neurons (2a). These studies demonstrated that PARP is present and can be activated in multiple subcellular compartments, particularly the 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 (2b). 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 this research, the laboratory developed an assay to quantify PARP activation in human tissues such as cerebrospinal fluid (CSF) (2c), and evaluated the impact of PARP single nucleotide polymorphisms in adults after severe TBI (2d).

2a. Du L, Zhang X, Han YY, Burke NA, Kochanek PM, Watkins SC, Graham SH, Carcillo JA, Szabo C, Clark RSB. 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

2b. *Lai Y, Chen Y, Watkins SC, Nathaniel PD, Guo F, Kochanek PM, Jenkins LW, Szabo C, Clark RSB. Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury. J Neurochem 2008;104:1700-1711. PMID: 17996029

2c. *Fink EL, Lai Y, Zhang X, Janesko-Feldman K, Adelson PD, Szabó C, Berger RP, Sarnaik AA, Kochanek PM, Clark RSB. 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. PMID: 18506195. PMC2560585

2d. *Sarnaik AA, Conley YP, Okonkwo DO, Barr TL, Fink EL, Szabo C, Kochanek PM, Clark RSB. Influence of PARP-1 polymorphisms in patients after traumatic brain injury. J Neurotrauma 2010;27:465-471. PMID:19925161. PMC2867630

 

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, http://sageke.sciencemag.org/cgi/content/full/2005/23/ns1), Nature (Suffocating cells show sex difference, M. Hopkin, http://www.nature.com/news/2004/040503/full/news040426-19.html), and highlighted in the 2014 NIH mandate to balance sex in cell and animal experiments (J. A. Clayton, F. S. Collins, http://www.nature.com/news/policy-nih-to-balance-sex-in-cell-and-animal-studies-1.15195). 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, a new R01 entitled Gender-Specific Treatment of Pediatric Cardiac Arrest was funded in 2005 after development of a novel model of pediatric asphyxial arrest in rodents with clinical fidelity including contemporary cardiopulmonary resuscitation, development of coma, and quantifiable cognitive deficits. Consistent with in vitro studies, a sex-dependent response to antioxidant therapies after cardiac arrest was observed (3d). Most recently, Dr. Clark with Dr. Hulya Bayir as multi-P.I. received a new R01 entitled Mitochondria-targeted Redox Therapy for Cerebral Ischemia in the Developing Brain, to study novel, mitochondria-targeting antioxidants in both male and female rats after cardiac arrest.

3a. *Satchell MA, Lai Y, Kochanek PM, Wisneiwski SR, Fink EL, Seidberg NA, Berger RP, DeKosky ST, Adelson PD, Clark RSB. 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 RSB. 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 RSB. Starving neurons show sex difference in autophagy. J Biol Chem 2009;284:2383-2396. PMID: 19036730. PMC2629091

3d. Manole MD, Kochanek PM, Foley LM, Hitchens TK, Bayir H, Alexander H, Garman R, Ma L, Hsia CJC, Ho C, Clark RSB. 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. PMID: 22126915. 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, respectively). 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, respectively). Despite their importance to pharmacokinetics and brain bioavailability of medicines used for standard care and potential neuroprotective agents, literally nothing is known regarding the role of these drug transporters in TBI, nor the response of these drug transporters to injury. Accordingly, how non-lipophilic drugs targeting the CNS cross the BBB and whether they maintain therapeutic concentrations are woefully underappreciated. As such, an R01 entitled “Overcoming Membrane Transporters to Improve CNS Drug Therapy” was funded in 2009 to address this scientific and clinical gap. This was in response to a Request for Proposals, and includes 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 (ClinicalTrials.gov identifier: NCT01322009). These studies take advantage of existing pharmacologic agents that increase bioavailability of neuroprotective agents in brains vulnerable after injury, e.g. probenecid. As a foundation for this work we have completed studies reporting the potential influence of genetic polymorphisms in ABC transporters after TBI (4a) and the impact of TBI on the ABC transporters ABCB1 and ABCC1 in humans (4b).

4a. *Cousar JL, Conley YP, Willyerd FA, Sarnaik AA, Puccio AM, Empey PE, Kochanek PM, Bell MJ, Okonkwo DO, Clark RSB. Influence of ATP-binding cassette polymorphisms on neurological outcome after traumatic brain injury. Neurocrit Care 2013;19:192-198. PMID: 23896815. PMC4332629

4b. *Willyerd FA, Empey PE, Philbrick A, Ikonomovic MD, Puccio AM, Kochanek PM, Okonkwo DO, Clark RSB. Expression of ATP-binding cassette transporters B1 and C1 after severe traumatic brain injury in humans. J Neurotrauma in press.

 

5. Other recently published or in press.

5a. Walko TD III, Di Caro V, Piganelli J, Billiar TR, Clark RSB, Aneja RK. Poly(ADP-ribose) polymerase-1 Sirtuin 1 functional interplay regulates LPS-mediated high mobility group box-1 secretion. Mol Med in press, 2015.

5b. Jackson TC, Du L, Janesko-Feldman K, Vagni VA, Dezfulian C, Poloyac SM, Jackson EK, Clark RSB, Kochanek PM. The nuclear splicing factor RNA binding motif 5 promotes caspase activation in human neuronal cells and increases after traumatic brain injury in mice. J Cereb Blood Flow Metab in press, 2015.

5c. *Newell E, Shellington DK, Simon DW, Bell MJ, Kochanek PM, Feldman K, Bayir H, Aneja RK, Carcillo JA, Clark RSB. Cerebrospinal fluid markers of macrophage and lymphocyte activation after traumatic brain injury in children. Pediatr Crit Care Med in press, 2015.

5d. *Da Silva YS, Hamilton MF, Horvat C, Fink EL, Palmer F, Nowalk AJ, Winger DS, Clark RSB. 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 in press, 2015.

5e. Shaik JSB, Clark RSB, Kochanek PM, Alexander H, Tudorascu DL, Poloyac SM, Manole MD. 20-HETE inhibition by HET0016 offers neuroprotection and increases cortical CBF in a pediatric rat asphyxia cardiac arrest model. J Cereb Blood Flow Metab in press, 2015.

5f. Au AK, Chen Y, Du L, Smith CM, Manole MD, Baltagi SA, Chu CT, Aneja RK, Bayir H, Kochanek PM, Clark RSB. Ischemia-induced autophagy contributes to neurodegeneration in cerebellar purkinje cells in the developing brain and in primary cortical neurons in vitro. Biochim Biophys Acta in press, 2015.

*Fellow, resident, or student as first author

 

Ongoing Research Support

R01 NS069247                    Clark (PI)                                                  9/30/09-6/30/15 NCE
Overcoming Membrane Transporters to Improve CNS Drug Therapy
The goals of this project are to augment brain bioavailability of neuroprotective agents by overcoming blood- brain and -CSF, and plasma membrane transporters.
Role: Principal Investigator
 
R01 NS084604                                     Clark/Bayir      (Multi-PI)                                                        3/15/14-12/31/18
Mitochondria-targeted Redox Therapy for Cerebral Ischemia in the Developing Brain
The goals of this project are to design, develop and test novel mitochondria-targeting nitroxide therapeutics toward improving neurological outcome after pediatric cardiac arrest.
Role: Principal Investigator (Multi-PI Bayir)
 
U01 NS081041                                    Bell (PI)                                                                                               7/1/13-6/30/18
Multiple Medical Therapies for Pediatric TBI: Comparative Effectiveness Approach
The goal of this project is to provide scientific evidence for future recommendations and guidelines leading to better clinical practices for pediatric patients with traumatic brain injury.
Role: Clinical Site PI
 
R01 GM098474                                   Aneja (PI)                                                                                            6/1/12-5/31/17
Regulation of LPS-Mediated HMGB1 Release by Poly(ADP-Ribose) Polymerase
This grant will explore mechanisms that regulate the secretion of a crucial late-mediator of sepsis, high mobility group box 1.
Role: Co-Investigator
 
R01 HD075760                                    Manole (PI)                                                                             7/1/13-6/30/18
CYP450-mediated CBF Dysregulation and Neurotoxicity in Pediatric Cardiac Arrest
This grant will explore molecular mechanisms of cerebral blood flow dysregulation after cardiac arrest in the developing brain
Role: Co-Investigator
 
T32 HD40686                                      Kochanek (PI)                                                                          7/1/06 – 6/30/15
Training in Pediatric Neurointensive Care and Resuscitation Research
The purpose of this training grant is to develop Clinician Scientists in Pediatric Neurointensive Care research. Role: Co-Principal Investigator
 
K08 NS069817                                     Dezfulian (PI)                                                                          9/15/10 - 8/31/15
Nitrite Based Neuroprotection after Cardiac Arrest
Role: Primary Sponsor for Cameron Dezfulian