Cytokine/chemokine mediated cross-talk between injured organs.
For the last six years I have been heavily involved in the wide spectrum of Genomics/Genetics studies including cardiovascular, pulmonary, and nephrology projects. My major objectives have been search for new molecular targets and unsuspected biological processes involved in complex responses to various pathologies. During 2001-2003 I was leading Genomic Data Analysis Unit of HOPGENE team (http://www.hopkins-genomics.org) at the Johns Hopkins Pulmonary Division under supervision of Skip Garcia. My research was devoted to gene expression profiling of lung tissues affected by injury, pulmonary hypertension, chronic obstruction, and asthma. In particular, my research was focused on acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). My Unit was conducting intensive genomics analysis of rat, mouse, and dog models of ALI. At the same time I was pursuing my own project focused on systemic effects of sepsis and ALI. Specifically I was interested in the mechanisms of cross-talk between injured lungs and other organs and its role in multiple organ failure using Bioinformatics approaches.
In 2005 I was hired by the Johns Hopkins Bayview Medical Center Lowe Family Genomics Core as a Genomics Project Director to lead their Data Analysis Module. While conducting and managing Genomics Data Analysis I continue my studies of the organ cross-talk. In collaboration with Dr. Hamid Rabb we designed studies to investigate kidney-lung communication during kidney injury.
Studies in patients have shown a strong association between acute kidney injury (AKI) and dysfunction of extra-renal organs, and more recently animal research has shown a significant causal effect of AKI on distant organ dysfunction. Based on evidence for elevation of levels of multiple proinflammatory effectors (cytokines, chemokines, reactive peptides) in blood during AKI, we hypothesize that excessive inflammatory response to AKI can leak proinflammatory molecules in circulation thus triggering tissue injurious effects in extra-renal organs. Given that the lung posses the largest capillary network in the body, its tissues are most exposed to circulating inflammation signaling molecules. The goal of my current studies is to investigate mechanisms of intra-organ signaling by cytokines/chemokines, and identify targets for potential therapeutic intervention. Given that there are more than 1000 known inflammation-associated signaling molecule, the direct (protein level) identification of these effectors is a time- and resource- demanding task. The genomics approach however significantly accelerates the discovery process and provides genome-wide information on majority of known inflammatory molecules.
I am planning to continue my research on organ cross-talk expanding investigation of systemic AKI effects to other organs including liver and brain. We recently have initiated collaborative effort with the National Institute on Aging (Bayview campus) to investigate systemic effects of AKI on brain in mouse model.
Grigoryev D.N., Liu M., Hassoun H.T., Cheadle C., Barnes K.C., Rabb H. (2008) The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol. 2008 Jan 30 [Epub ahead of print]
Grigoryev D.N., Ma S-F., Shimoda L.A., Johns R.A., Lee B., and Garcia J.G.N. (2007) Exon-based mapping of microarray probes: Recovering differential gene expression signal in underpowered hypoxia experiment. Mol and Cell Probes 21(2):134-9
Hassoun H.T., Grigoryev D.N., Lie M.L., Liu M., Cheadle C., Tuder R.M., and Rabb H. (2007) Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol. 293(1):F30-40.
Gao L., Tsai Y.J., Grigoryev D.N., Barnes K.C. (2007) Host defense genes in asthma and sepsis and the role of the environment. Curr Opin Allergy Clin Immunol. 7(6):459-67.
Grigoryev D.N., Liu M., Cheadle C., Barnes K.C., and Rabb H. (2006) Genomic profiling of kidney ischemia reperfusion reveals expression of specific alloimmunity-associated genes: linking "immune" and "non-immune" injury events. Transplantation Proc. 38(10):3333-6
Simon B.A., Easley R.B., Grigoryev D.N., Ma S-F., Ye S.Q., Lavoie T., Tuder R.M., Garcia J.G. (2006) Microarray analysis of regional cellular responses to local mechanical stress in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 291(5):L851-61
Grigoryev D.N., Ma S-F., Ye S.Q., Simon B., and Garcia J.G.N. (2005) In vitro identification and in silico utilization of interspecies sequence similarities using GeneChip technology. BMC Genomics, 6(1):62.
Ma S-F., Grigoryev D.N., Taylor A.D., Nonas S., Sammani S., Ye S.Q., Garcia J.G.N. (2005) Bioinformatic identification of novel early stress response genes in rodent models of lung injury. Am. J. Physiol. Lung Cell Mol. Physiol., 289(3):L468-77.
Grigoryev D.N., Finigan J.H., Hassoun P.M., and Garcia J.G.N. Searching for gene candidates in acute lung injury. (2004) Critical Care Med. 8(6):440-7.
Grigoryev D.N., Ma S-F., Ye S.Q., Irizarry R.A., Quackenbush J., and Garcia J.G.N. (2004) Orthologous gene expression profiling in multi-species models: search for candidate genes. Genome Biology 5(5):R34
Dmitry N. Grigoryev MD, PhD
Instructor in Medicine
Genomics Project Director
Johns Hopkins Bayview Medical Center Genetic Research Facility (Director: Dr. Kathleen C. Barnes)
Last Updated February 2008