Ryan Jordan Stark, M.D.

Assistant Professor

ryan.stark@vanderbilt.edu

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Faculty Appointments
Assistant Professor of Pediatrics
Education
M.D., MEDICINE, George Washington University, Washington, District of ColumbiaB.S., University of Southern California, Los Angeles, California
Office Address
2200 Children's Way
5121 Doctors' Office Tower
Nashville, TN 37232
Research Description
Our current work focuses on the inflammatory effect of infection on an often overlooked component of innate immunity, the endothelium. Specifically, we are investigating how endothelial cells are affected during infection, with specific focus on endothelial nitric oxide synthase (eNOS) dysfunction. Nitric oxide produced by eNOS regulates many key functions of endothelial cells, namely vasomotor tone, cellular adhesion to myeloid cells and endothelial permeability. During severe systemic infections, known as sepsis, these functions are disturbed and contribute to the clinical findings of sepsis such as hypotension, capillary leak and microvascular thrombosis. We are currently trying to understand how infections induce changes in eNOS function, which will provide a framework towards combating the detrimental effects of endothelial dysfunction during sepsis.

Additionally, we are examining how priming of the endothelium with a toll-like receptor 4 (TLR4) agonist, monophosphoryl lipid a (MPLA), alters the pro-inflammatory responses of activated endothelial cells in a models of burn-injury and acquired infections. TLRs are a major class of pattern recognition receptors crucial for innate immunity. There are several TLRs known in humans that respond to different pathogen associated molecular patterns (PAMPs). TLR4 is unique by its ability to cross-react with other TLRs due to its two downstream signaling cascades, MyD88 and TRIF. Currently we are exploring how MPLA can retrain endothelial cells to become tolerant to subsequent infectious challenges.

The long term goal of this work is to understand the mechanisms of endothelial dysfunction during infections and find modalities to mitigate the effects of infection on endothelial activation through the use of immunomodulators.

Links:
http://news.vanderbilt.edu/2016/01/immune-tolerance-endothelial-cells/
Clinical Description
I am a member of the Pediatric Critical Care Division of Vanderbilt University School of Medicine. My clinical interests are related to my research endeavors, with specific interests in inflammatory responses related to infectious and traumatic injuries.
Research Keywords
Endothelial Dysfunction, Inflammation, Toll-like Receptors (TLR), Nitric Oxide (NO)
Clinical Research Keywords
Sepsis, Systemic Inflammatory Response Syndrome (SIRS), Burn Injury
Publications
Krispinsky LT, Stark RJ, Parra DA, Luan L, Bichell DP, Pietsch JB, Lamb FS. Endothelial-Dependent Vasomotor Dysfunction in Infants After Cardiopulmonary Bypass. Pediatr Crit Care Med [print-electronic]. 2019 Jun 6/26/2019; PMID: 31246738, DOI: 10.1097/PCC.0000000000002049, ISSN: 1529-7535.

Fukuda S, Ihara K, Bohannon JK, Hernandez A, Patil NK, Luan L, Stothers C, Stark R, Prough DS, Herndon DN, Sherwood ER, Enkhbaatar P. Monophosphoryl Lipid A Attenuates Multiorgan Dysfunction During Post-Burn Pseudomonas Aeruginosa Pneumonia In Sheep. Shock [print-electronic]. 2019 Apr 4/26/2019; PMID: 31045990, DOI: 10.1097/SHK.0000000000001364, ISSN: 1540-0514.

Thompson KB, Krispinsky LT, Stark RJ. Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies. Mil Med Res. 2019 Apr 4/24/2019; 6(1): 11. PMID: 31014397, PMCID: PMC6480837, PII: 10.1186/s40779-019-0202-0, DOI: 10.1186/s40779-019-0202-0, ISSN: 2054-9369.

Koch SR, Choi H, Mace EH, Stark RJ. Toll-like receptor 3-mediated inflammation by p38 is enhanced by endothelial nitric oxide synthase knockdown. Cell Commun. Signal. 2019 Apr 4/15/2019; 17(1): 33. PMID: 30987646, PMCID: PMC6466662, PII: 10.1186/s12964-019-0345-3, DOI: 10.1186/s12964-019-0345-3, ISSN: 1478-811X.

Choi H, Stark RJ, Raja BS, Dikalova A, Lamb FS. Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNFa receptor endocytosis. Am. J. Physiol. Heart Circ. Physiol [print-electronic]. 2019 Mar 3/29/2019; PMID: 30925081, DOI: 10.1152/ajpheart.00741.2018, ISSN: 1522-1539.

Stark RJ, Koch SR, Choi H, Mace EH, Dikalov SI, Sherwood ER, Lamb FS. Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling. FASEB J [print-electronic]. 2017 Oct 10/23/2017; PMID: 29061842, PII: fj.201700410R, DOI: 10.1096/fj.201700410R, ISSN: 1530-6860.

Luan L, Patil NK, Guo Y, Hernandez A, Bohannon JK, Fensterheim BA, Wang J, Xu Y, Enkhbaatar P, Stark R, Sherwood ER. Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A. Sci Rep. 2017 Jan 1/5/2017; 7: 40050. PMID: 28053314, PII: srep40050, DOI: 10.1038/srep40050, ISSN: 2045-2322.

Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ. Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Transl Res [print-electronic]. 2016 Aug 8/8/2016; PMID: 27567430, PII: S1931-5244(16)30158-X, DOI: 10.1016/j.trsl.2016.08.001, ISSN: 1878-1810.

Stark RJ, Choi H, Koch SR, Fensterheim BA, Lamb FS, Sherwood ER. Endothelial cell tolerance to lipopolysaccharide challenge is induced by Monophosphoryl lipid A. Clin. Sci [print-electronic]. 2015 Dec 12/15/2015; PMID: 26669797, PII: CS20150592, DOI: 10.1042/CS20150592, ISSN: 1470-8736.

Choi H, Dikalova A, Stark RJ, Lamb FS. C-Jun N-terminal kinase attenuates TNFa signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells. Free Radic. Biol. Med [print-electronic]. 2015 Sep; 86: 219-27. PMID: 26001727, PII: S0891-5849(15)00226-9, DOI: 10.1016/j.freeradbiomed.2015.05.015, ISSN: 1873-4596.

Stark R, Choi H, Koch S, Lamb F, Sherwood E. Monophosphoryl lipid A inhibits the cytokine response of endothelial cells challenged with LPS. Innate Immun [print-electronic]. 2015 Aug; 21(6): 565-74. PMID: 25540284, PMCID: PMC4480205, PII: 1753425914564172, DOI: 10.1177/1753425914564172, ISSN: 1753-4267.

Stark RJ, Shekerdemian LS. Estimating intracardiac and extracardiac shunting in the setting of complex congenital heart disease. Ann Pediatr Cardiol. 2013 Jul; 6(2): 145-51. PMID: 24688231, PMCID: PMC3957443, PII: APC-6-145, DOI: 10.4103/0974-2069.115259, ISSN: 0974-2069.

Stark RJ, Naik-Mathuria BJ, Lam FW, Olutoye OO, Sutton VR, Shekerdemian LS. Extracorporeal membrane oxygenation support of a severe metabolic crisis in a child with methylmalonic acidemia. ASAIO J. 2012 Jul; 58(4): 438-9. PMID: 22711065, DOI: 10.1097/MAT.0b013e31825a223c, ISSN: 1538-943X.

Stark RJ, Aghakasiri N, Rumbaut RE. Platelet-derived Toll-like receptor 4 (Tlr-4) is sufficient to promote microvascular thrombosis in endotoxemia. PLoS ONE [print-electronic]. 2012; 7(7): e41254. PMID: 22911769, PMCID: PMC3401143, PII: PONE-D-12-14054, DOI: 10.1371/journal.pone.0041254, ISSN: 1932-6203.

Shen W, Falahati R, Stark R, Leitenberg D, Ladisch S. Modulation of CD4 Th cell differentiation by ganglioside GD1a in vitro. J. Immunol. 2005 Oct 10/15/2005; 175(8): 4927-34. PMID: 16210594, PII: 175/8/4927, ISSN: 0022-1767.