The Center for Critical Care is a leading program at The Ohio State University Medical Center. Physicians and researchers are undertaking systems biology tools to study the complex network in human diseases, such as pulmonary fibrosis, sepsis, and asthma, and identify biomarkers for diagnosis, prevention and therapeutic intervention.
Led by Clay Marsh, MD, researchers in the program focus on the biological variability of each patient to establish links between genetic and protein changes leading to perturbations in molecular pathways in Intensive Care Unit (ICU) patients, focusing on sepsis. Sepsis is a life-threatening disease characterized by an imbalance in host regulatory pathways. It is a leading cause of death in patients in the ICU and represents a tremendous opportunity to define a prediction model to identify patients with the risk of this serious complication of infectious disease. The Marsh laboratory focuses on profiling these patients’ genetics at the microRNA and mRNA level, along with proteomics and incorporation of informatics support through Ohio State’s College of Public Health, Ohio State’s Center for Biostatistics, Battelle, and the Institute for Systems Biology. This laboratory also applies these tools to patients with pulmonary fibrosis, breast cancer and lung cancer.
Susheela Tridandapani, PhD, and her team are studying mechanisms of innate host response to infectious agents using a combination of cellular and molecular studies. The molecular approaches include genome wide analyses of cells and animals exposed to the infectious stimuli, along with immunological and biochemical approaches. Their goal is to identify molecular targets for therapeutic intervention in infectious and inflammatory disease. Mark Wewers, MD, and his laboratory are focused on the role of caspase-1 in sepsis and outcomes. Recent studies have shown that caspase-1 deficient mice are protected from death caused by intraperitoneal bacteria. More importantly, the caspase-1 effect appears to be due to its role in causing the programmed cell death of splenic lymphocytes. Thus, future studies directed at inhibiting caspase-1 may provide novel approaches to treating sepsis. Elliott Crouser, MD, and his laboratory are focusing on the role of mitochondria abnormalities associated with sepsis. Research in this program focuses on defining the role of mitochondria function as a driver of multiple organ system failure.
Andrea Doseff, PhD, and her team are seeking to understand the role of caspase activation in inflammatory disease and cancer. They determined that post-translational activation of caspase-3 is critical in the activation of cellular apoptosis.
The Patrick Nana-Sinkam, MD, laboratory seeks to understand the molecular regulation of lung cancer using microRNA profiling and to define biomarkers in patient’s serum that may help predict disease occurrence and spread. Phil Diaz, MD, who leads Ohio State’s emphysema program, has been a principle investigator in the NIH-sponsored lung volume reduction surgery trial and is currently a PI in the long-term oxygen treatment trial, which focuses on understanding the role of oxygen in the outcomes of patients with COPD. John Mastronarde, MD, is a PI for the NIH and ALA sponsored Asthma Clinical Trials Network, which seeks to define clinical applications to facilitate execution of practice in patients with asthma.
The Center also has established collaborative relationships with the Institute for Behavioral Medicine Research, studying the role of stress in critical care and lung disease and focusing on correlating network activation in humans and animals suffering behavioral stress to directly link stress to disease genesis and progression. The Center also has a collaborative relationship with the tumor microenvironment program that focuses on determining the effect of organ matrix on cellular trafficking and activation.
In collaboration with Jyoti Kamal, PhD, in Information Technology, the Center has built an ICU minimum dataset that collects information about all ICU patients and the care they receive. In addition, the Center established a biorepository of patients with sepsis and developed an information warehouse (IW) application that collects information about patients enrolled in a sepsis registry. This unique biorepository and IW tool allow studies that link genetic variations to long-term outcome of septic patients, enabling discovery of biomarkers that potentially can be used to guide therapies and to predict outcomes. These tools are supported by collaborations with Ohio State’s College of Public Health, Center for Biostatistics and Mathematical Biosciences Institute, as well as Battelle and the Institute for Systems Biology, to provide the computational biology and informatics support to effectively analyze the data.
References
Bringardner BD, Baran CP, Eubank TD, and Marsh CB The Role of Inflammation in the Pathogenesis of Idiopathic Pulmonary Fibrosis Antioxidants & Redox Signaling. 2007,ahead of print. doi:10.1089/ars.1897.
Magro CM, Waldman WJ, Knight DA, Allen JN, Nadasdy T, Frambach GE, Ross P, Marsh CB Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies. Hum Immunol. 2006; 67(4-5):284-97.
Bhatt N, Baran CP, Allen J, Magro C, and Marsh CB Promising pharmacologic innovations in treating pulmonary fibrosis. Curr Opin Pharmacol., 2006;6(3):284-292.
Ganesan LP, Joshi T, Fang H, Kutala VK, Roda J, Trotta R, Lehman A, Kuppusamy P, Byrd JC, Carson WE, Caligiuri MA, and Tridandapani S Fc?R-induced production of superoxide and inflammatory cytokines is differentially regulated by SHIP through its influence on PI3K and/or Ras/Erk pathways. Blood, 2006;15:108(2): 718–725.
Rajaram MV, Ganesan LP, Parsa KV, Butchar JP, Gunn JS, Tridandapani S Akt/Protein kinase B modulates macrophage inflammatory response to Francisella infection and confers a survival advantage in mice. J Immunol., 2006;1:177(9): 6317-24.
Butchar JP, Rajaram MV, Ganesan LP, Parsa KV, Clay CD, Schlesinger LS, Tridandapani S Francisella tularensis induces IL-23 production in human monocytes. J Immunol., 2007; 1;178(7):4445-54.
Gavrilin MA, Bouakl IJ, Knatz NL, Duncan MD, Hall MW, Gunn JS, Wewers MD Internalization and phagosome escape required for Francisella to induce human monocyte IL-1beta processing and release. Proc Natl Acad Sci USA, 2006;3;103(1):141-6.
Sarkar A, Duncan M, Hart J, Hertlein E, Guttridge DC, Wewers MD ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions. J Immunol., 2006;15;176(8):4979-86.
Seshadri S, Duncan MD, Hart JM, Gavrilin MA, Wewers MD Pyrin levels in human monocytes and monocyte-derived macrophages regulate IL-1beta processing and release. J Immunol., 2007;15;179(2):1274-81.
Joshi MS, Julian MW, Huff JE, Bauer JA, Xia Y, Crouser ED Calcineurin regulates myocardial function during acute endotoxemia. Am J Respir Crit Care Med., 2006;1;173(9):999-1007.
Crouser ED, Julian MW, Huff JE, Struck J, Cook CH Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis. Crit Care Med., 2006;34(9):2439-46.
Voss OH, Kim S, Wewers MD, Doseff AI Regulation of monocyte apoptosis by the protein kinase Cdelta-dependent phosphorylation of caspase-3. J Biol Chem., 2005;29;280(17):17371-9.
Voss OH, Batra S, Kolattukudy SJ, Gonzalez-Mejia ME, Smith JB, Doseff AI Binding of caspase-3 prodomain to heat shock protein 27 regulates monocyte apoptosis by inhibiting caspase-3 proteolytic activation. J Biol Chem., 2007;24;282(34):25088-99.
Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, Guttridge DC, Grotewold E, Doseff AI Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-kappaB through the suppression of p65 phosphorylation. J Immunol., 2007;15;179(10):7121-7.
Nana-Sinkam SP and Geraci MW MicroRNA in lung cancer. J Thorac Oncol., 2006;1(9):929-31.
To locate more information pertaining to the above referenced articles please visit the PubMed database.