Research Interests:Transgenic approaches to study adenosine signaling

Adenosine is an extracellular signaling nucleoside that has profound effects on cellular growth, differentiation and homeostasis. Adenosine levels are tightly regulated in tissues and cells by the enzyme adenosine deaminase (ADA), that is responsible for the irreversible deamination of adenosine to inosine. The regulatory actions of adenosine are mediated by membrane receptors that are classified as P1 purinergic receptors. Four distinct subtypes of adenosine receptors have been identified and are termed A1, A2a, A2b, and A3 adenosine receptors. Adenosine receptors are tightly coupled to effector enzymes such as adenylate cyclase and phospholypase C, by guanine nucleotide regulatory proteins. Thus, adenosine signaling can have input into multiple intracellular signal transduction pathways. However, a clear understanding of the role of adenosine signaling in development and disease are lacking.

By genetically engineering mice that are deficient in the enzyme ADA, we have created animals that possess a widespread elevation in adenosine levels, allowing us to screen for phenotypes that may result from perturbed adenosine signaling. One of the more prominent phenotypes observed was severe pulmonary inflammation and lung damage, reminiscent of that seen in humans with asthma. Current efforts in the lab are focused on determining the role of adenosine signaling in this mouse model of experimental asthma. This includes identifying the cellular distribution of receptor subtypes and the characterization of downstream effector systems. In addition to asthma, the lab is also interested in the role adenosine signaling plays in lung development and in the pathogenesis of lung fibrosis. Various transgenic and knockout mouse strategies are utilized to study aspects of the adenosine signaling pathway in these processes.

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Banerjee SK, Young HWJ, Volmer JB, Blackburn MR (2002) Gene expression profiling in inflammatory airway disease associated with elevated adenosine. Am J Phys Lung Cell Mol Physiol, 282:L169-L182.

Chunn JL, Young HWJ, Zhong H, Banerjee SK, Colasurdo GN, Blackburn MR (2001) Adenosine-dependent airway inflammation and hyperresponsiveness in partially adenosine deaminase deficient mice. J Immunol 167:4676-4685.

Zhong H, Chunn JL, Volmer JB, Fozard JL, Blackburn MR (2001) Adenosine mediated mast cell degranulation in adenosine deaminase-deficient mice. J Pham Exp Ther 298:433-440.

Blackburn MR, Aldrich M, Volmer JB, Chen W, Kelly S, Hershfield MS, Datta SK, Kellems RE (2000) The use of enzyme therapy to regulate the metabolic and phenotypic consequences of adenosine deaminase deficiency in mice: Differential impact on pulmonary and immunologic abnormalities. J Biol Chem 275:32114-32121.

Blackburn MR, Volmer JB, Thrasher JC, Crosby JR, Lee JJ, Kellems RE (2000) Metabolic consequences of adenosne deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation and airway obstruction. J Exp Med 192:159-170.

Blackburn MR, Wubah J, Chunn JL, Thompson LT, Knudsen TB (1999) Transitory expression of the A2b adenosine receptor during implantation chamber devel-opment. Developmental Dynamics 216:127-136.

Blackburn MR, Datta SK, Kellems RE (1998) Adenosine deaminase deficient mice generated using a two stage genetic engineering strategy exhibit a combined immunodeficiency. J Biol Chem 273:5093-5100.

Blackburn MR, Knudsen TB, Kellems RE (1997) Genetically engineered mice demonstrate that adenosine deaminase is essential for early postimplantation development. Development 124:3089-3097.

Program Affiliation:
Program in Biochemistry and Molecular Biology