Skip to main content

Nariman Balenga, PhD

Academic Title:

Assistant Professor

Primary Appointment:

Surgery

Location:

BRB 10-027

Phone (Primary):

410-706-3261

Education and Training

  • University of Tehran (Iran), M.Sc., Medical Biotechnology, 2005
  • Medical University of Graz (Austria), Ph.D., Molecular Medicine (Pharmacology), 2010
  • Postdoctoral Research Fellowships: Medical University of Graz (Austria), 2010-2011; National Institutes of Health/NIAID (Bethesda, MD), 2011-2014; University of Maryland School of Medicine (Baltimore), 2014-2015

Biosketch

I received my Master degree in Medical Biotechnology from University of Tehran (Iran) in 2005, investigating the efficiency of biodegradable nanoparticles for DNA vaccine administration in mouse models of allergy. I then started my PhD in Molecular Medicine (Pharmacology) at the Institute of Experimental and Clinical Pharmacology at Medical University of Graz (Austria), where I studied potential drug targets (G Protein-Coupled Receptors, GPCR) involved in inflammation.

After graduation in 2010, I started a 3-year postdoctoral work at Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH/NIAID). At this position, I studied the impact of Regulators of G-protein Signaling (RGS) on the pathogenesis of asthma ex vivo and in vivo. This was followed by a 1-year postdoctoral work at University of Maryland School of Medicine exploring the mechanisms by which RGS proteins disturb the body calcium homeostasis. In 2015, I joined the Division of General & Oncologic Surgery at the Department of Surgery, University of Maryland School of Medicine as an assistant professor.

Research/Clinical Keywords

Endocrine Dysfunction, GPCR Signaling and Function, Cancer, Asthma Pathogenesis

Highlighted Publications

Balenga, N., Koh, J., Azimzadeh, P., Hogue, J., Gabr, M., Stains, J.P., Olson, J.A. (2019) Parathyroid-targeted overexpression of Regulator of G-Protein Signaling 5 (RGS5) causes hyperparathyroidism in transgenic mice. Journal of Bone and Mineral Research. DOI:10.1002/jbmr.3674

Balenga, N.*, Azimzadeh, P., Hogue, J.A., Staats, P.N., Shi, Y., Koh, J., Dressman, H., Olson, J.A. (2016) Orphan Adhesion GPCR GPR64/ADGRG2 is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling. Journal of Bone and Mineral Research.32(3):654-666* Corresponding Author

Balenga, N., Klichinsky, M., Zhao, M., Jude, J., Laviolette, M., Panettieri, R. A. Jr., Druey K.M. (2015) A fungal protease allergen provokes airway hyperresponsiveness in asthma. Nature Communications. 6: 6763-6776.

Balenga, N.*, Martínez-Pinilla, E., Kargl, J., Schröder, R., Platzer, W., Zamarbide, M., M Pérez-Ortiz, J., Kostenis, E., Waldhoer, M., Heinemann, A., and Franco, R. (2014) Heteromerization of GPR55 and CB2R modulates receptor signaling. British Journal of Pharmacology. 171 (23): 5387-406.* Corresponding Author

Balenga, N., Jester, W., Jiang, M., Panettieri, R. A. Jr. and Druey, K.M. (2014) Loss of RGS5 uncouples inflammation and airway hyperresponsiveness in mice. Journal of Allergy and Clinical Immunology. 134 (2):451-9.

Balenga, N.*, Aflaki, E., Kargl, J., Platzer, W., Schröder, R., Blättermann, S., Brown A. J., Kostenis, E., Heinemann, A. and Waldhoer, M. (2011) GPR55 regulates the cannabinoid 2 receptor-mediated responses in human blood neutrophils. Cell Research 21(10): 1452-1469.* Corresponding Author

Balenga, N., Henstridge, C. M., Kargl, J. and Waldhoer, M. (2011) Pharmacology, Signaling and Physiological Relevance of the G Protein-coupled Receptor 55. Advances in Pharmacology, Pharmacology of G protein coupled receptors. 62: 251-277. Book Chapter

Henstridge, C. M., Balenga, N., Ford, L. A., Ross, R. A., Waldhoer, M. and Irving, A. J. (2009) The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB Journal 23: 183-193.

 

Additional Publication Citations

Azimzadeh, P., Olson, J.A., Balenga, N. (2017) Reporter gene assays for investigating GPCR signaling. Methods in Cell Biology. In Press.
 
Basu, T., Seyedmousavi, S., Sugui, J.A., Balenga, N., Zhao, M., Chung, K.J.K., Biardel, S., Laviolette, M., Druey, K.M. (2017) Aspergillus fumigatus alkaline protease 1 (Alp1/Asp f13) in the airways correlates with asthma severity.  The Journal of Allergy and Clinical Immunology. In Press.
 
Madigan, L.A., Wong, G.S., Gordon, E.M., Chen, W.S., Balenga, N., Koziol-White, C.J., Panettieri Jr., R.A., Levine, S.J., Druey, K.M. (2017) RGS4 Overexpression in Lung Attenuates Airway Hyper-responsiveness in Mice.  American Journal of Respiratory Cell and Molecular Biology. In Press
 
Kargl, J., Balenga, N., Parzmair, GP., Brown, AJ., Heinemann, A. and Waldhoer, M. (2012) The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55. Journal of Biological Chemistry 287 (53): 44234-48.
 
Yang, Z., Balenga, N., Cooper, P. R., Damera, G., Edwards, Brightling, C. E., Panettieri, R. A. Jr. and Druey, K.M. (2012) RGS5 inhibits bronchial smooth muscle contraction in fatal asthma. American Journal of Respiratory Cell and Molecular Biology 46 (6): 823-832.
 
Kargl, J., Balenga, N., Platzer, W., Martini, L., Whistler, J. L. and Waldhoer, M. (2011) The GPCR - associated sorting protein 1 regulates ligand-induced down-regulation of GPR55. British Journal of Pharmacology 165(8): 2611-9.
 
Aflaki, E., Balenga, N., Luschnig-Schratl, P., Wolinski, H., Povoden, S., Chandak, P. G., Bogner-Strauss, J. G., Eder, S., Konya, V., Kohlwein, S., Heinemann, A. and Kratky, D. (2011) Impaired Rho GTPase activation abrogates cell polarization and migration in macrophages with defective lipolysis. Cellular and Molecular Life Sciences 68(23):3933-47.
 
Henstridge, C. M., Balenga, N., Kargl, J., Andradas, C., Brown, A. J., Irving, A. J., Sanchez, C., Waldhoer, M. (2011) Recent developments in the physiology and pathology of the lysophosphatidylinositol-sensitive receptor GPR55. Molecular Endocrinology 25: 1835-48.
 
Henstridge, C. M., Balenga, N., Schröder, R., Kargl, J. K., Platzer, W., Martini, L., Arthur, S., Penman, J., Whistler, J. L., Kostenis, E., Waldhoer, M. and Irving, A. J. (2010) GPR55 ligands promote receptor coupling to multiple signaling pathways. British Journal of Pharmacology 160: 604-614.
 
Waldeck-weiermair, M., Zoratti, C., Osibow, K., Balenga, N., Goessnitzer, E., Waldhoer, M., Malli, R. and Graier, W. F. (2008) Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression. Journal of Cell Science 121: 1704-1717.
 
Balenga, N., Zahedifard, F., Weiss, R., Sarbolouki, M. N., Thalhamer, J. and Rafati, S. (2006) Protective efficiency of dendrosomes as novel nano-sized adjuvants for DNA vaccination against birch pollen allergy. Journal of Biotechnology 124: 602-614.

Research Interests

The main focus of my lab is on the function of G Protein-Coupled Receptors (GPCRs) in health and disease. GPCRs represent the largest superfamily of receptors in human genome and are the target of about 35% of currently marketed medicines prescribed for a variety of diseases (cancer, hypertension, asthma and pain). These 7-transmembrane integral proteins are expressed on the surface of many cell types, which makes them accessible for biologics and small molecules as novel interventions. They transmit various extracellular cues including hormones, chemokines, neurotransmitters and ions to intracellular signaling pathways involved in development, proliferation and migration.

Despite the plethora of efforts in the academia and industry, the function of many GPCRs in human cells and tissues are poorly understood. Moreover, to date there are around 140 orphan GPCRs, i.e. receptors without known endogenous ligands.

My lab exploits biochemical, pharmacological and translational approaches to:

  1. Unravel the signaling cascades and function of GPCRs and their signaling partners in inflammatory and metabolic diseases.
  2. Delineate the function of Adhesion GPCRs, aberrantly expressed in tumors.
  3. Deorphanize GPCRs implicated in cancer and asthma.


Current Projects:

Calcium-Sensing Receptor and RGS Proteins in Parathyroid Tumors

Primary hyperparathyroidism (PHPT) is characterized by inappropriate parathyroid hormone (PTH) secretion by neoplastic parathyroid cells. Uncoupling of calcium sensing by the parathyroid calcium-sensing GPCR (CASR) to negatively regulate PTH secretion is the hallmark of the disease and may actually drive abnormal parathyroid growth. Although calcimimetic compounds (positive allosteric modulator of CASR) have shown some utility, the response in PHPT patients is incomplete, not experienced by all patients and has only a modest effect on reducing the PTH level without changing the bone mineral density. The relationship between uncontrolled cell proliferation and abnormal hormone secretion is a fundamental and poorly elucidated issue in endocrine cell neoplasia. We have found that i) regulator of G-protein signaling 5 (RGS5) is overexpressed in a subset of parathyroid tumors and can inhibit CASR signaling, ii) RGS5 knockout mice have abnormally low basal and calcium-sensitive PTH levels. We are developing a parathyroid-specific RGS5 overexpressing mouse line and will be investigating the mechanisms by which RGS5 may promote parathyroid neoplasia and PTH hypersecretion.

Balenga, N.*, Azimzadeh, P., Hogue, J.A., Staats, P.N., Shi, Y., Koh, J., Dressman, H., Olson, J.A. (2016) Orphan Adhesion GPCR GPR64/ADGRG2 is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling. Journal of Bone and Mineral Research.32(3):654-666* Corresponding Author

Koh, J., Dar M., Untch BR., Dixit D., Shi Y., Yang Z., Adam MA., Dressman H., Wang X., Gesty-Palmer D., Marks JR., Spurney R., Druey K.M., Olson JA Jr. (2011) Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor. Molecular Endocrinology. 25(5): 867-76.

Balenga, N., Jester, W., Jiang, M., Panettieri, R. A. Jr. and Druey, K.M. (2014) Loss of RGS5 uncouples inflammation and airway hyperresponsiveness in mice. Journal of Allergy and Clinical Immunology. 134 (2):451-9.

Yang, Z., Balenga, N., Cooper, P. R., Damera, G., Edwards, Brightling, C. E., Panettieri, R. A. Jr. and Druey, K.M. (2012) RGS5 inhibits bronchial smooth muscle contraction in fatal asthma. American Journal of Respiratory Cell and Molecular Biology 46 (6): 823-832.

 

Adhesion GPCRs in Tumors

Although adhesion GPCRs (aGPCRs) are the second largest family of GPCRs in humans (33 members), they are the least studied group. This family is distinct from the rest of superfamily due to a very long extracellular region and its hybrid structure. aGPCRs go through a proteolysis process during biosynthesis, leaving an N-terminal fragment that in most cases stays bound to the 7-transmembrane region and the rest of C-terminal fragment via non-covalent interactions. These receptors contain many cell and ECM-interacting domains in the N-terminal segment, the reason to be called “adhesion” GPCR. aGPCRs have been implicated in tumor formation and metastasis. We are currently conducting expression analysis in human tumor databases at RNA and protein levels and will explore the role of certain aGPCRs by generating knockout or overexpressing mice. This translational approach will hopefully shed light on the physiological and pathophysiological roles of this poorly studied family of GPCRs. In long term, we will exploit multiple epitopes on the long N-terminal fragment of aGPCRs as a therapeutic biologic-based approach.

Balenga, N.*, Azimzadeh, P., Hogue, J.A., Staats, P.N., Shi, Y., Koh, J., Dressman, H., Olson, J.A. (2016) Orphan Adhesion GPCR GPR64/ADGRG2 is Overexpressed in Parathyroid Tumors and Attenuates Calcium-Sensing Receptor-Mediated Signaling. Journal of Bone and Mineral Research.32(3):654-666* Corresponding Author

 

Novel Targets in Asthma Therapy

Allergic asthma is a chronic disease where exposure of the airway epithelium to otherwise innocuous molecules (allergens) induces production of cytokines/chemokines, which in turn recruit leukocytes, leading to airway remodeling. Inflammatory mediators released in these conditions, namely acetylcholine and histamine, bind to their cognate GPCRs and trigger a cytosolic calcium-mediated contraction of airway smooth muscle cells (ASM). Recently, we showed that the proteolytic activity of a typical allergen (Alp1 of a ubiquitous fungus Aspergillus fumigatus) permits diffusion into the submucosal ASM layer, where it disrupts the interactions of ASM and extracellular matrix (ECM). Alp1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca2+ sensitivity and exaggerated bronchoconstriction in response to GPCR agonists. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyperresponsiveness. Future studies will be directed to 1. Identify molecular components of ASM excitation/contraction coupling pathways regulated by protease allergens and test them in vivo; 2. Evaluate protease inhibitors and specific antibodies as novel interventions in mouse models of asthma.

Balenga, N., Klichinsky, M., Zhao, M., Jude, J., Laviolette, M., Panettieri, R. A. Jr., Druey K.M. (2015) A fungal protease allergen provokes airway hyperresponsiveness in asthma. Nature Communications. 6: 6763-6776.

Balenga, N., Jester, W., Jiang, M., Panettieri, R. A. Jr. and Druey, K.M. (2014) Loss of RGS5 uncouples inflammation and airway hyperresponsiveness in mice. Journal of Allergy and Clinical Immunology. 134 (2):451-9.

 

Deorphanizing aGPCRs

More than two thirds of aGPCRs are orphan and due to their interesting expression profiles and roles in development, inflammation and cancer we will use in vitro approaches to discover their cognate ligands. First, we will develop feasible robust assays to detect their minuscule signaling to downstream second messengers or transcription factors. Then we will expand our assays to high-throughput formats and will screen available compound libraries.

Awards and Affiliations

  • 2019: Early Career Award in Translational and Clinical Pharmacology (ASPET)
  • 2012: Fellows Award for Research Excellence (FARE 2013) from the National Institutes of Health, MD, USA
  • 2010: Young Investigators Award of the Federation of European Pharmacological Societies (EPHAR)
  • 2008: Young Investigators Award of the Austrian Pharmacological Society (APHAR)
  • 2007-2010: Ph.D. fellowship from Medical University of Graz, Austria
  • 1999-2005: Fellowship for Exceptional Talents from Ministry of Science, Research and Technology of Iran

Grants and Contracts

  • Parathyroid Tumor Clonal Status as a Biomarker in Primary Hyperparathyroidism, R01, NCI (Co-Investigator)

  • PhRMA Foundation Research Starter Grant in Translational Medicine and Therapeutics (PI)

  • American Cancer Society Institutional Research Grant (PI)

Professional Activity

  • American Society for Pharmacology and Experimental Therapeutics (ASPET)
  • Associate Member of Program in Oncology, Hormone Responsive Cancers, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
  • Program in Molecular and Structural Biology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
  • Member of Adhesion-GPCR Consortium

Lab Techniques and Equipment

Equipment 

  • Inverted microscope equipped with: encoded motorized stage, tile-scanning/stitching, cMOS 16.25 megapixels color/monochrome camera
  • Automated cell counter
  • Multimode microplate reader (Fluorescence, Absorbance, Luminescence, Fluorescence Polarization, Time-Resolved FRET with liquid handling)

 

In vitro Techniques

  • FLIPR intracellular calcium release assay in 96- and 384-well formats
  • cAMP and IP-One HTRF assays
  • Reporter gene luciferase assays
  • MAPK, Small GTPases assays
  • Gene cloning, qPCR
  • Immunofluorescence (IF), Immunohistochemistry (IHC)
  • Bright field, Fluorescence and Confocal microscopy on slides and 96-well format with quantitative analysis packages

 

In vivo/Ex vivo Techniques

  • Mouse Model of Primary Hyperparathyroidism
  • Acute and Chronic Mouse Models of Asthma
  • Live Precision-Cut Lung Slices/Contraction assay

Links of Interest

  • GPCRdb offers reference data and easy-to-use web tools and diagrams for a multidisciplinary audience investigating GPCR function, drug design or evolution: http://gpcrdb.org/
  • The Adhesion-GPCR Consortium: http://www.adhesiongpcr.org/
  • CASRdb is dedicated to serving the Internet community by providing information on published mutations and polymorphisms of the calcium-sensing receptor (CASR): http://www.casrdb.mcgill.ca/
  • The world's largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer: https://cancer.sanger.ac.uk/cosmic/
  • A comprehensive, high-quality and freely accessible resource of protein sequence and functional information: http://www.uniprot.org/