Hydar Ali, Ph.D.

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Graduate Group Affiliations

Contact information
Robert Schattner Center
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 such as Asthma and Anaphylaxis

Research Summary:

Asthma is a chronic inflammatory disease, which is associated with the recruitment of mast cells to the lung and their activation. It is well known that aggregation of high affinity IgE receptors (FcepsilonRI) on mast cells and the subsequent mediator release contributes to the development of allergic asthma. However, emerging evidence suggests that transactivation of G protein coupled receptors (GPCRs) for the complement component C3a contributes to the exacerbation of allergic diseases. The main focus of our laboratory has been to delineate how G protein coupled receptor kinases (GRKs) and the adaptor molecule β-arrestin regulate C3a receptor function in mast cells. We unexpectedly found that GRK2 and β-arrestin2 serve as novel adaptor proteins to promote IgE-mediated mast cell chemotaxis, degranulation and cytokine gene expression. We are currently utilizing both in vitro and in vivo approaches to delineate how GRK2 and β-arrestin2 regulate FcepsilonRI signaling in mast cells to modulate allergic asthma.

Surface epithelial cells, when activated by pathogen-associated molecular patterns (PAMPs) release small cationic antibacterial peptides (AMPs), known as defensins and cathelicidins. These AMPs display potent antimicrobial activity, modulate immune responses and likely participate in the exacerbation of allergic diseases such as asthma and urticaria. Recently, we made the unexpected observation that AMPs activate human mast cells via a novel GPCR (Mas-related gene X2; MrgX2). Most interestingly, we found that unlike C3a receptor, MrgX2 is resistant to regulation by GRK2 or β-arrestin-2. It is noteworthy that unlike human mast cells, murine mast cells do not express MrgX2 and are resistant to activation by AMPs. We are currently engrafting human CD34+ hematopoietic stem cells (HSCs) into severely immune-deficient mice. In addition to human immune system, these “HUMANIZED MICE” develop human tissue mast cells are responsive to AMPs for activation in vivo. We are currently using the humanized mouse model to determine the role of MrgX2 and its signaling on anaphylaxis and asthma in vivo.

Selected Publications

Subramanian, H. Gupta, K. Parameswaran, N. Ali, H.: Regulation of Fc[epsilon]RI signaling in mast cells by G protein coupled receptor kinase-2 and its RH domain. The Journal of biological chemistry DOI:10.1074/jbc.M113.523969, June 2014.

Subramanian Hariharan, Gupta Kshitij, Lee Donguk, Bayir Arzu K, Ahn Harry, Ali Hydar: β-Defensins activate human mast cells via Mas-related gene X2. Journal of immunology (Baltimore, Md. : 1950) 191(1): 345-52, Jul 2013.

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.

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.

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: 07/23/2014
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