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Hydar Ali, Ph.D.
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Graduate Group Affiliations
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- Pharmacology 5c
- Immunology e
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Contact information
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Robert Schattner Center
19 346 Levy Building
38 240 South 40th Street
Philadelphia, PA 19104
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19 346 Levy Building
38 240 South 40th Street
Philadelphia, PA 19104
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Office: (215) 573-1993
34 Fax: (215) 573-2050
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34 Fax: (215) 573-2050
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Email:
alih@upenn.edu
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alih@upenn.edu
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Publications
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Education:
21 a B.Sc. c
3b University College London, England, 1982.
21 a Ph.D. 24 (Immunology/Pharmacology) c
31 University of London, UK, 1986.
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Permanent link21 a B.Sc. c
3b University College London, England, 1982.
21 a Ph.D. 24 (Immunology/Pharmacology) c
31 University of London, UK, 1986.
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ed The goal of the Ali lab is to utilize pre-clinical humanized mouse models to delineate how novel G Protein Coupled Receptor (GPCR) signaling in mast cells promotes/modulates neurogenic inflammation and immune-mediated disorders.
8
19 RESEARCH DETAILS:
1c9 Approximately 35% of all FDA-approved drugs target seven transmembrane (7TM) domain GPCRs. In addition to G proteins, these receptors interact with GPCR kinases (GRKs) and the adapter protein β-arrestin. Different GPCR agonists may signal selectively via G proteins (G protein-biased), GRK (GRK-biased) or β-arrestin (β-arrestin-biased). Novel therapeutic approach involves targeting biased signaling in a variety of immune and non-immune cells.
8
544 Mast cells are tissue-resident immune cells that are found in close proximity to blood vessels and nerve endings and serve as sentinel cells against microbial infections. However, they are best known for their roles in anaphylaxis and allergic disorders such as atopic dermatitis and allergic asthma. The pathologic effects of mast cells are thought to mediated via the activation of high affinity IgE receptors (FceRI). We found that human mast cells express a novel GPCR known as MRGPRX2 (mouse counterpart, MrgprB2). MrgprB2 and MRGPRX2 are activated by the same set of agonists such as the neuropeptides, antimicrobial peptides and FDA-approved peptidergic drugs. However, many specific antagonists developed against human MRGPRX2 do not block MrgprB2 function. We therefore developed a "humanized" preclinical mouse model where the endogenous MrgprB2 was replaced with human MRGPRX2. We are leveraging these mice to introduce disease-associated missense mutations and to modulate the expression of GRKs and β-arrestins. We propose to utilize these preclinical models to delineate how biased signaling through MRGPRX2 contributes to innate immunity/host defense and how dysregulation of receptor expression/function leads to anaphylaxis, drug hypersensitivity, neurogenic inflammation and immune-mediated disorders, as outlined below.
a
25 -Innate Immunity/Host Defense
14 -Anaphylaxis
32 -Immediate Drug Hypersensitivity Reactions
20 -Neurogenic Inflammation
10 -Asthma
42 -Skin inflammation (Rosacea, Psoriasis, Atopic Dermatitis)
1b -Ulcerative colitis
19 -Periodontitis
8
1c CURRENT LAB MEMBERS:
32 Shaswati Chaki, Ph.D. (Research Associate)
39 Sangita Sutradhar Ph.D. (Postdoctoral Researcher)
33 Puja Dutta, Ph.D. (Postdoctoral Researcher)
1e Reshma Davis (Student)
22 Kaream Al-Jabban (Student)
1f Harsha Meduru (Student)
1d Bahar Azadi (Student)
8
1b AVAILABLE PROJECTS:
10d Projects are available for interested undergraduate, dental and graduate students to study mast cell MRGPRX2/FceRI regulation in vitro and neurogenic inflammation, asthma, cutaneous inflammatory disorders, anaphylaxis and drug-induced hypersensitivity reactions.
26 29
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Description of Research Expertise
24 RESEARCH INTERESTS:ed The goal of the Ali lab is to utilize pre-clinical humanized mouse models to delineate how novel G Protein Coupled Receptor (GPCR) signaling in mast cells promotes/modulates neurogenic inflammation and immune-mediated disorders.
8
19 RESEARCH DETAILS:
1c9 Approximately 35% of all FDA-approved drugs target seven transmembrane (7TM) domain GPCRs. In addition to G proteins, these receptors interact with GPCR kinases (GRKs) and the adapter protein β-arrestin. Different GPCR agonists may signal selectively via G proteins (G protein-biased), GRK (GRK-biased) or β-arrestin (β-arrestin-biased). Novel therapeutic approach involves targeting biased signaling in a variety of immune and non-immune cells.
8
544 Mast cells are tissue-resident immune cells that are found in close proximity to blood vessels and nerve endings and serve as sentinel cells against microbial infections. However, they are best known for their roles in anaphylaxis and allergic disorders such as atopic dermatitis and allergic asthma. The pathologic effects of mast cells are thought to mediated via the activation of high affinity IgE receptors (FceRI). We found that human mast cells express a novel GPCR known as MRGPRX2 (mouse counterpart, MrgprB2). MrgprB2 and MRGPRX2 are activated by the same set of agonists such as the neuropeptides, antimicrobial peptides and FDA-approved peptidergic drugs. However, many specific antagonists developed against human MRGPRX2 do not block MrgprB2 function. We therefore developed a "humanized" preclinical mouse model where the endogenous MrgprB2 was replaced with human MRGPRX2. We are leveraging these mice to introduce disease-associated missense mutations and to modulate the expression of GRKs and β-arrestins. We propose to utilize these preclinical models to delineate how biased signaling through MRGPRX2 contributes to innate immunity/host defense and how dysregulation of receptor expression/function leads to anaphylaxis, drug hypersensitivity, neurogenic inflammation and immune-mediated disorders, as outlined below.
a
25 -Innate Immunity/Host Defense
14 -Anaphylaxis
32 -Immediate Drug Hypersensitivity Reactions
20 -Neurogenic Inflammation
10 -Asthma
42 -Skin inflammation (Rosacea, Psoriasis, Atopic Dermatitis)
1b -Ulcerative colitis
19 -Periodontitis
8
1c CURRENT LAB MEMBERS:
32 Shaswati Chaki, Ph.D. (Research Associate)
39 Sangita Sutradhar Ph.D. (Postdoctoral Researcher)
33 Puja Dutta, Ph.D. (Postdoctoral Researcher)
1e Reshma Davis (Student)
22 Kaream Al-Jabban (Student)
1f Harsha Meduru (Student)
1d Bahar Azadi (Student)
8
1b AVAILABLE PROJECTS:
10d Projects are available for interested undergraduate, dental and graduate students to study mast cell MRGPRX2/FceRI regulation in vitro and neurogenic inflammation, asthma, cutaneous inflammatory disorders, anaphylaxis and drug-induced hypersensitivity reactions.
26 29
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23e Al Hamwi, G., Alnouri, MW, Verdonck, S., Leonczak, P., Chaki, S., Riedel, YK., Marx, D., Clemens, S., Frischbutter, S., Kolkhir, P., Matthey, M., Namasivayam, V., Gattner, S., Thimm, D., Sylvester, K., Wolf, K., Kremer, AE., De Jonghe, S., Wenzel, D., Maurer, M., Ali, H., Herdewijn, P., and Müller, CE: Subnanomolar MAS-related G protein coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models. Signal Transduction and Targeted Therapy 2025 Notes: PMCID: PMC12010006.
fd Bawazir, M., Sutradhar, S., Roy, S and Ali, H. : MRGPRX2 facilitates IgE-mediated systemic anaphylaxis in a newly established knock-in mouse model. J Allergy Clin Immunol 55, 2025.
12f Amponnawarat, A, Marcelo D. T. Torres, M, Krishnan, R., de la Fuente-Nunez, C and Ali, H: Synthetic peptides targeting MrgprB2/MRGPRX2 display anti-infective potential. Cell Biomaterials 1: 100088, 2025 Notes: PMCID: PMC12010006.
1c7 Galeas-Pena, M, Lyons, J Llivichuzhca-Loja, D, Everman, S. Yaghi, G., , White, K., Sutradhar, S, Robinson, T , Owings, A, Dhaliwal, N , Carlye, A , Konnikova, L, Ali, H, Glover, SG: MRGPRX2-expressing mast cells are increased in the GI tract of individuals with active inflammatory bowel disease and hereditary α-tryptasemia. Front in Allergy 2025 Notes: PMCID: PMC12868144.
144 Chaki, S., Amponnawarat, A, Levenstein, B, Hui, Y., Oskeritzian, C and Ali, H. : Glatiramer acetate induces mast cell degranulation via MRGPRX2, implications for local and systemic adverse reactions. Allergy 79: 758-761, 2024 Notes: PMCID:PMC10922971.
106 Roy, S, Alkanfari, I, Chaki, S and Ali, H: Role of MrgprB2 in Rosacea-like Inflammation in Mice: Modulation by β-arrestin2. J Invest Dermatol 142: 2988-2997, 2022 Notes: PMCID:PMC9634617.
11b Chompunud Na Ayudhya, C., Amponnawarat, A., Roy, S., Oskeritzian, C. A., Ali, H.: MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants. Cells 10(1), 2021.
11f Thapaliya, M., Chompunud Na Ayudhya, C., Amponnawarat, A., Roy, S., Ali, H.: Mast Cell-Specific MRGPRX2: a Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Curr Allergy Asthma Rep 21(1): 3, 2021.
116 Gupta, K., Kotian, A., Subramanian, H., Daniell, H., Ali, H.: Activation of human mast cells by retrocyclin and protegrin highlight their immunomodulatory and antimicrobial properties. Oncotarget 2015.
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Selected Publications
115 Omari-Manaa1, S, Aharonov, R, Galli, SJ , Ali, H and Sagi-Eisenberg, R: Distinct phosphoinositide signatures orchestrate FcεRI versus MRGPRX2 mast cell secretion. iScience 2026 Notes: PMCID: PMC13090623.23e Al Hamwi, G., Alnouri, MW, Verdonck, S., Leonczak, P., Chaki, S., Riedel, YK., Marx, D., Clemens, S., Frischbutter, S., Kolkhir, P., Matthey, M., Namasivayam, V., Gattner, S., Thimm, D., Sylvester, K., Wolf, K., Kremer, AE., De Jonghe, S., Wenzel, D., Maurer, M., Ali, H., Herdewijn, P., and Müller, CE: Subnanomolar MAS-related G protein coupled receptor-X2/B2 antagonists with efficacy in human mast cells and disease models. Signal Transduction and Targeted Therapy 2025 Notes: PMCID: PMC12010006.
fd Bawazir, M., Sutradhar, S., Roy, S and Ali, H. : MRGPRX2 facilitates IgE-mediated systemic anaphylaxis in a newly established knock-in mouse model. J Allergy Clin Immunol 55, 2025.
12f Amponnawarat, A, Marcelo D. T. Torres, M, Krishnan, R., de la Fuente-Nunez, C and Ali, H: Synthetic peptides targeting MrgprB2/MRGPRX2 display anti-infective potential. Cell Biomaterials 1: 100088, 2025 Notes: PMCID: PMC12010006.
1c7 Galeas-Pena, M, Lyons, J Llivichuzhca-Loja, D, Everman, S. Yaghi, G., , White, K., Sutradhar, S, Robinson, T , Owings, A, Dhaliwal, N , Carlye, A , Konnikova, L, Ali, H, Glover, SG: MRGPRX2-expressing mast cells are increased in the GI tract of individuals with active inflammatory bowel disease and hereditary α-tryptasemia. Front in Allergy 2025 Notes: PMCID: PMC12868144.
144 Chaki, S., Amponnawarat, A, Levenstein, B, Hui, Y., Oskeritzian, C and Ali, H. : Glatiramer acetate induces mast cell degranulation via MRGPRX2, implications for local and systemic adverse reactions. Allergy 79: 758-761, 2024 Notes: PMCID:PMC10922971.
106 Roy, S, Alkanfari, I, Chaki, S and Ali, H: Role of MrgprB2 in Rosacea-like Inflammation in Mice: Modulation by β-arrestin2. J Invest Dermatol 142: 2988-2997, 2022 Notes: PMCID:PMC9634617.
11b Chompunud Na Ayudhya, C., Amponnawarat, A., Roy, S., Oskeritzian, C. A., Ali, H.: MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants. Cells 10(1), 2021.
11f Thapaliya, M., Chompunud Na Ayudhya, C., Amponnawarat, A., Roy, S., Ali, H.: Mast Cell-Specific MRGPRX2: a Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Curr Allergy Asthma Rep 21(1): 3, 2021.
116 Gupta, K., Kotian, A., Subramanian, H., Daniell, H., Ali, H.: Activation of human mast cells by retrocyclin and protegrin highlight their immunomodulatory and antimicrobial properties. Oncotarget 2015.
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