Researchers have developed a method to design drugs that efficiently block rather than activate critical cell receptors which may help avoid adverse medication outcomes.
Soberman Laboratory: Roy Soberman, MD
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About the Lab
The overall focus of my laboratory is to understand signal integration and macromolecular organization in cells of the immune system, and how these processes are linked to control the amplification of the immune response. In inflammatory diseases of the kidney, and in all immune disease, myeloid cells and lymphocytes are exposed to a large number of "kinase-based" signals from cytokines, interleukins, and growth factors, and also to signals from G-protein coupled receptors such as those for leukotrienes and chemokines. These combinations change, depending on the microenvironment of the cells. Each of these receptors engage a variety of intracellular pathways to allow these cells to perform the appropriate function in tissue environments. We focus on how cells integrate signaling responses between these different pathways, with the goal of identifying how cellular organization translates into defined biological phenotypes in health and disease. Our long-term goal is to apply this knowledge to human immune and inflammatory diseases. We are focusing on three projects that relate to the amplification of biological responses in myeloid cells, including dendritic cells, mast cells, monocytes, and neutrophils.
Project 1 is the identification and regulation of discrete multiprotein membrane complexes, in vivoand ex vivo, that regulate the formation of the bioactive lipids leukotrienes (LT) and prostaglandins, and how these complexes are regulated in inflammatory diseases. We have found that leukotriene formation is regulated by the signal-dependent organization of multiprotein complexes on the nuclear envelope and ER. We are utilizing a combination of molecular imaging, and biochemical analysis combined with protein Mass-spectrometry to determine the composition of these complexes and how their composition determines LT production ex vivo and in vivo.
In Project 2, we have identified the mechanisms by which human and mouse myeloid cells inactivate the chemotactic lipid LTB4. This process is regulated in humans by a member of the 4F family of cytochrome P450s, CYP4F3A and in mice by its orthologue CYP4f18. This project relates to both the regulation of the expression and function of this protein in vivo. We are particularly focusing on the role of redox-sensitive transcription factors in regulating the expression of this protein and also the function of dendritic cells.
Project 3 is to identify novel signal integrating proteins. One approach we use is to screen for proteins whose intracellular trafficking requires the engagement of specific receptors from different classes. We have identified two unique proteins in antigen-presenting dendritic cells and other myeloid cells using this approach.
Christmas P, Carlesso N, Shang H, Cheng SM, Weber BM, Preffer FL, Scadden D and Soberman RJ. Myeloid expression of cytochrome P450 4F3 is determined by a lineage specific alternative promoter. J Biol Chem. 2003. 278: 25133-25142.
Christmas P, Ursino SR, Fox JW, and Soberman RJ. Expression of the CYP4F3 gene. Tissue specific splicing and alternate promoters generate high and low Km forms of leukotriene B4w-hydroxylase. J Biol Chem. 1999. 274: 21191 - 21199.
Christmas P, Weber BM, McKee M, Brown D, and Soberman RJ. Membrane localization and topology of leukotriene C4 synthase. J Biol Chem. 2002. 277: 28902 - 28908.
Christmas P, Jones JP, Patten CJ, Rock DA, Zheng Z, Cheng SM, Weber BM, Carlesso N, Scadden DT, Rettie AE, and Soberman RJ. Alternative splicing determines the function of CYP4F3 by switching substrate specificity.J Biol Chem. 2001. 276: 38166 - 38172.
Christmas P, Fox JW, Ursino SR, and Soberman RJ. Differential localization of 5- and 15-lipooxygenases to the nuclear envelope in RAW macrophages.J Biol Chem. 1999. 274: 25594 - 25598.
Soberman RJ. The expanding network of redox signaling: new observations, complexities, and perspectives. J Clin Invest. 2003. 111: 571-574.
Soberman RJ and Christmas P. The organization and consequences of eicosanoid signaling. J Clin Invest. 2003. 111: 1107 - 1113.
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