Ryan Stark
Last active: 4/16/2021

Profile

The purpose of my work is to understand the mechanisms through which acute inflammatory responses alter vascular function and contribute to critical illness. Further, I am interested in discovering ways that limit the negative impact inflammation has on the endothelium and associated vascular system. Previous work I have done has focused on the mechanisms involved in clot formation during exposure to endotoxin and cecal ligation and perforation, which are models of sepsis. With this work, we found unique roles of complement 5a receptor and toll-like receptor 4 (TLR4) in endotoxin mediated microvascular thrombosis. We further investigated how endothelial cells are affected during infection, with specific focus on endothelial nitric oxide synthase (eNOS) dysfunction. Furthermore, we examined how priming of the immune system with a TLR4 agonist, monophosphoryl lipid a (MPLA), altered the pro-inflammatory responses of activated endothelial cells with secondary infectious challenges. Current work is based on a particularly interesting and novel finding of prior work; eNOS can modulate the endothelial response to inflammation independent of nitric oxide (NO) and this effect is partially dependent on direct interactions with mitogen-activated protein kinases (MAPKs). Exploration of these direct interactions among intracellular proteins of inflammation has been achieved using a new confocal technique, proximity ligation assays, which allow us to examine eNOS-MAPK interactions, among other intracellular interactions of interest, in both human cells and animal models. In addition, we have recently developed a novel eNOS-mimetic peptide that we have shown can attenuate the response to TLR4 challenge. Lastly, we have begun to explore endothelial dysfunction in humans using a technique called laser doppler perfusion monitoring with iontophoresis coupled to human blood and plasma samples with the hope of finding unique vascular signatures that can be studied in the laboratory. These techniques allow us to propose new and clinically relevant questions related to three integrated aims in the current proposal exploring the role and relationship of eNOS and sirtuins, key mediators of endothelial homeostasis, in the vascular perturbation of acute systemic inflammation and MODS development. Our research program is related to the long-term goal of my work which is to understand the mechanisms of acute vascular dysfunction and find modalities that allow for identification and future treatment. I have been involved in academic research throughout my career and have the determination and focus, as well as the clinical background to help answer questions that arise in critically ill patients at the bedside. I have also been involved in mentoring younger trainees with the hope of inspiring them to think critically and pose new and interesting questions on how we approach critical illness. By continuing our research program, I hope to continue these pursuits by asking clinically relevant questions, investigating them with trainees in the laboratory and hospital settings, and ultimately finding answers that can be brought back to patients to help temper the severity of illness and reduce morbidity and mortality.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Apoptosis signal-regulating kinase 1 (ASK1) inhibition reduces endothelial cytokine production without improving permeability after toll-like receptor 4 (TLR4) challenge. Miller MR, Koch SR, Choi H, Lamb FS, Stark RJ (2021) Transl Res : 115-128
    › Primary publication · 33857660 (PubMed) · PMC8328918 (PubMed Central)
  2. The Inverse Relationship Between Endothelium-Dependent Vasodilation and Blood Pressure is Lost After Cardiopulmonary Bypass. Stark RJ, Krispinsky LT, Lamb FS (2021) J Cardiovasc Transl Res
    › Primary publication · 33835431 (PubMed) · PMC8501160 (PubMed Central)
  3. TNFα and Reactive Oxygen Signaling in Vascular Smooth Muscle Cells in Hypertension and Atherosclerosis. Lamb FS, Choi H, Miller MR, Stark RJ (2020) Am J Hypertens 33(10): 902-913
    › Primary publication · 32498083 (PubMed) · PMC7577645 (PubMed Central)
  4. Neuronal ASIC1A As a Cerebral pH Sensor: Bringing the Flow. Stark RJ, Choi H, Lamb FS (2019) Circ Res 125(10): 921-923
    › Primary publication · 31647772 (PubMed) · PMC6993881 (PubMed Central)
  5. Endothelial-Dependent Vasomotor Dysfunction in Infants After Cardiopulmonary Bypass. Krispinsky LT, Stark RJ, Parra DA, Luan L, Bichell DP, Pietsch JB, Lamb FS (2020) Pediatr Crit Care Med 21(1): 42-49
    › Primary publication · 31246738 (PubMed) · PMC8098768 (PubMed Central)
  6. Monophosphoryl Lipid a Attenuates Multiorgan Dysfunction During Post-Burn Pseudomonas Aeruginosa Pneumonia in Sheep. Fukuda S, Ihara K, Bohannon JK, Hernandez A, Patil NK, Luan L, Stothers C, Stark R, Prough DS, Herndon DN, Sherwood ER, Enkhbaatar P (2020) Shock 53(3): 307-316
    › Primary publication · 31045990 (PubMed) · PMC6937402 (PubMed Central)
  7. Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies. Thompson KB, Krispinsky LT, Stark RJ (2019) Mil Med Res 6(1): 11
    › Primary publication · 31014397 (PubMed) · PMC6480837 (PubMed Central)
  8. Toll-like receptor 3-mediated inflammation by p38 is enhanced by endothelial nitric oxide synthase knockdown. Koch SR, Choi H, Mace EH, Stark RJ (2019) Cell Commun Signal 17(1): 33
    › Primary publication · 30987646 (PubMed) · PMC6466662 (PubMed Central)
  9. Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNFα receptor endocytosis. Choi H, Stark RJ, Raja BS, Dikalova A, Lamb FS (2019) Am J Physiol Heart Circ Physiol 316(6): H1528-H1537
    › Primary publication · 30925081 (PubMed) · PMC6620688 (PubMed Central)
  10. Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling. Stark RJ, Koch SR, Choi H, Mace EH, Dikalov SI, Sherwood ER, Lamb FS (2018) FASEB J 32(2): 945-956
    › Primary publication · 29061842 (PubMed) · PMC5888395 (PubMed Central)
  11. Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A. Luan L, Patil NK, Guo Y, Hernandez A, Bohannon JK, Fensterheim BA, Wang J, Xu Y, Enkhbaatar P, Stark R, Sherwood ER (2017) Sci Rep : 40050
    › Primary publication · 28053314 (PubMed) · PMC5215261 (PubMed Central)
  12. Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Koch SR, Lamb FS, Hellman J, Sherwood ER, Stark RJ (2017) Transl Res : 53-67.e4
    › Primary publication · 27567430 (PubMed) · PMC5253081 (PubMed Central)
  13. Endothelial cell tolerance to lipopolysaccharide challenge is induced by monophosphoryl lipid A. Stark RJ, Choi H, Koch SR, Fensterheim BA, Lamb FS, Sherwood ER (2016) Clin Sci (Lond) 130(6): 451-61
    › Primary publication · 26669797 (PubMed) · PMC4744094 (PubMed Central)
  14. c-Jun N-terminal kinase attenuates TNFα signaling by reducing Nox1-dependent endosomal ROS production in vascular smooth muscle cells. Choi H, Dikalova A, Stark RJ, Lamb FS (2015) Free Radic Biol Med : 219-27
    › Primary publication · 26001727 (PubMed)
  15. Monophosphoryl lipid A inhibits the cytokine response of endothelial cells challenged with LPS. Stark R, Choi H, Koch S, Lamb F, Sherwood E (2015) Innate Immun 21(6): 565-74
    › Primary publication · 25540284 (PubMed) · PMC4480205 (PubMed Central)
  16. Estimating intracardiac and extracardiac shunting in the setting of complex congenital heart disease. Stark RJ, Shekerdemian LS (2013) Ann Pediatr Cardiol 6(2): 145-51
    › Primary publication · 24688231 (PubMed) · PMC3957443 (PubMed Central)
  17. Platelet-derived Toll-like receptor 4 (Tlr-4) is sufficient to promote microvascular thrombosis in endotoxemia. Stark RJ, Aghakasiri N, Rumbaut RE (2012) PLoS One 7(7): e41254
    › Primary publication · 22911769 (PubMed) · PMC3401143 (PubMed Central)
  18. Extracorporeal membrane oxygenation support of a severe metabolic crisis in a child with methylmalonic acidemia. Stark RJ, Naik-Mathuria BJ, Lam FW, Olutoye OO, Sutton VR, Shekerdemian LS (2012) ASAIO J 58(4): 438-9
    › Primary publication · 22711065 (PubMed)
  19. Modulation of CD4 Th cell differentiation by ganglioside GD1a in vitro. Shen W, Falahati R, Stark R, Leitenberg D, Ladisch S (2005) J Immunol 175(8): 4927-34
    › Primary publication · 16210594 (PubMed)