Hydar Ali

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Graduate Group Affiliations

Contact information
346 Levy Building
240 South 40th Street
Philadelphia, PA 19104
Office: (215) 573-1993
Fax: (215) 573-2050
Education:
B.Sc.
University College London, England, 1982.
Ph.D. (Immunology/Pharmacology)
University of London, UK, 1986.
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Description of Research Expertise

Research Interests:

Mast Cell Signaling in the Regulation of Allergic Diseases and Innate Immunity

Research Summary:

G protein coupled receptors (GPCRs) belong to one of the largest known groups of integral membrane receptor proteins. Not surprisingly, GPCRs have been exploited extensively for drug targets and their intracellular signaling pathways have been studied in great detail. Although it is well established that cross-linking of high affinity IgE receptors (FcRI) on mast cells and the subsequent mediator release leads to the pathogenesis of allergic asthma, emerging evidence suggests that mast cell GPCRs play an important role in modulating the disease process. The main research focus of our lab has been to delineate the pathways involved in the regulation GPCR signaling in human mast cells. In one project, we are interested in determining how C3a receptor phosphorylation by G protein coupled receptor kinases (GRKs) and the recruitment of adapter molecules (β-arrestins) regulate the activation of human mast cells. Our in vitro studies have clearly demonstrated that C3a receptor signaling in human mast cells are regulated differently by GRKs and β-arrestins than GPCRs that are expressed in many non-inflammatory cells. Currently we are using an adoptive transfer procedure to reconstitute mast cell-deficient mice with in vitro-derived murine mast cells expressing genetically modified GRKs and β-arrestins. These studies will allow us to determine how regulation of GPCR signaling specifically in mast cells modulates allergic diseases in vivo.

Surface epithelial cells, when activated by pathogen-associated molecular patterns (PAMPs) release small cationic antibacterial peptides (AMPs), known as defensins and cathelicidins. These peptides display potent antimicrobial activities, modulate immune responses, participate in angiogenesis and wound healing. In addition, they promote tumor metastasis and are implicated in a variety of chronic inflammatory diseases. Surprisingly, the cellular and molecular mechanisms via which these AMPs promote their diverse biological functions remain unknown. Recently, we made the unexpected observation that AMPs activate human mast cells via a new family of GPCRs (Mas-related genes; Mrgs) that are known to be selectively expressed in dorsal root ganglia. There receptors are not expressed in circulating white blood cells or tissue macrophages. Furthermore, there are no murine counterparts of human Mrg receptors. Most interestingly, we found that functions of these receptors are regulated differently by GRKs and β-arrestins than most of the known GPCRs. We are using both in vitro and in vivo approaches to study the regulation of these receptors. For in vitro signaling studies, we are utilizing primary human mast cells that natively express Mrgs and transfected human mast cell lines that do not natively express these receptors. For in vivo studies, we are using lentiviral transduction procedure to express human Mrgs in murine bone mast cells. Our plan is to adoptively transfer these murine mast cells expressing human GPCRs into mast cell-deficient mice. This approach will allow us to determine the role of human Mrg receptors in mast cells on allergic diseases and innate immunity.

Another focus of our research is to delineate the role of epithelial cell-derived cytokines on mast cell-mediated allergic diseases. These studies are based on the recent finding that a newly identified epithelial cell-derived cytokine IL-33, which activates a previously known orphan receptor ST2, and synergizes with antigen/IgE for Th2 cytokine generation in mast cells. We are testing the novel idea that the adapter molecule MyD88 is critical for the synergy between IL-33 and IgE for Th2 cytokine generation and allergic inflammation. For these studies, we are using retrovirus to transduce bone marrow progenitor cells with genetically modified MyD88 and to differentiate these cells into mast cells ex vivo. Our goal is to identify the motifs on MyD88 that regulates the synergy between IL-33 and IgE in mast cells. We are also adoptively transferring mast cells expressing genetically modified MyD88 into mast cell-deficient mice to determine how mast cell-specific modulation of MyD88 regulates allergic inflammation in vivo.

Selected Publications

Subramanian Hariharan, Gupta Kshitij, Ali Hydar: Roles for NHERF1 and NHERF2 on the regulation of C3a receptor signaling in human mast cells. PloS one 7(12): e51355, 2012.

Gupta Kshitij, Subramanian Hariharan, Klos Andreas, Ali Hydar: Phosphorylation of C3a receptor at multiple sites mediates desensitization, β-arrestin-2 recruitment and inhibition of NF-κB activity in mast cells. PloS one 7(10): e46369, 2012.

Subramanian Hariharan, Gupta Kshitij, Guo Qiang, Price Ryan, Ali Hydar: Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization. The Journal of biological chemistry 286(52): 44739-49, Dec 2011.

Shenker Bruce J, Ali Hydar, Boesze-Battaglia Kathleen: PIP3 regulation as promising targeted therapy of mast-cell-mediated diseases. Current pharmaceutical design 17(34): 3815-22, Nov 2011.

Kashem Sakeen W, Subramanian Hariharan, Collington Sarah J, Magotti Paola, Lambris John D, Ali Hydar: G protein coupled receptor specificity for C3a and compound 48/80-induced degranulation in human mast cells: roles of Mas-related genes MrgX1 and MrgX2. European journal of pharmacology 668(1-2): 299-304, Oct 2011.

Subramanian Hariharan, Kashem Sakeen W, Collington Sarah J, Qu Hongchang, Lambris John D, Ali Hydar: PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Molecular pharmacology 79(6): 1005-13, Jun 2011.

Kashem, SW, Subramanian, H., Collington, S Maggoti, P, Lambris, JD and Ali, H. : G protein coupled receptor specificity for C3a and compound 48/48-induced degranulation in human mast cells: roles of Mas-related genes MrgX1 and MrgX2. Eur. J. Pharm. 668: 299-304, 2011.

Shenker, BJ, Ali, H and Boesze-Battaglia, K. : PIP3 regulation as promising targeted therapy of mast-cell-mediated diseases. Current Pharmaceutical Design Page: In Press, 2011.

Vibhuti, A., Gupta, K., Subramanian, H, Quo, Q and Ali, H. : Distinct and shared roles of β-arrestin-1 and β-arrestin-2 on the regulation of C3a receptor signaling in human mast cells. PLoS ONE 6(5): e19585, 2011.

Guo, Q, Subramanian, H, Gupta, K and Ali, H. : Regulation of C3a receptor signaling in human mast cells by G Protein coupled receptor kinases. PLoS ONE 6: e22559, 2011.

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Last updated: 07/03/2013
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