Adenosine deaminase (ADA) deficiency was the first of the human immunodeficiencies for which the underlying biochemical defect was discovered. Subsequent studies revealed that ADA deficiency is the most severe of the immunodeficiencies, affecting the production of all lymphocyte populations. However, despite many years of investigation the molecular basis of the severe combined immunodeficiency resulting from ADA deficiency is not understood. The principle long-range goal of research proposed here is to understand the role of ADA in the development and function of the immune system. Another long-range goal is to understand the role of adenosine signaling in disease. The pursuit of these goals is facilitated by the availability of ADA- deficient transgenic mice that display most features seen in ADA- deficient humans. In addition to immunodeficiency, ADA-deficient humans and mice are characterized by skeletal abnormalities, renal problems, pulmonary insufficiency, neurological impairment, and (in mice) cardiac hypertrophy. ADA plays a critical role in controlling the concentration of adenosine, thereby potentially affecting many areas of intercellular signaling influenced by adenosine. In the absence of ADA the uncontrolled accumulation of adenosine may lead to widespread activation of adenosine receptors on a variety of cells with detrimental effects on numerous areas of physiology. The other ADA substrate, 2'- deoxyadenosine, may be cytotoxic by interference with a number of critical metabolic pathways. In considering the complexity of the phenotypes associated with ADA deficiency in humans and mice, it is likely that some features are attributable to alterations in adenosine signaling, whereas others are due to 2'- deoxyadenosine-induced metabolic disturbances. ADA-deficient mice have tremendous potential as investigative tools in lymphocyte immunobiology and adenosine signaling. The utility of ADA-deficient mice is aided significantly by the ability to use ADA enzyme therapy as a convenient experimental strategy to regulate the metabolic consequences of ADA deficiency and differentially correct abnormalities associated with ADA deficiency. To address the long-range goals of this research we have organized four specific aims around the following four questions.
AIM I. What is the molecular basis of impaired T cell development in ADA-deficient mice? AIM II. What is the impact of ADA deficiency on B cell development and function? AIM III. What is the impact of ADA deficiency on natural killer cell development and function? AIM IV. What role does adenosine signaling play in the non-immune features associated with ADA deficiency?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046207-17
Application #
6626064
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
1992-07-15
Project End
2007-03-31
Budget Start
2003-05-01
Budget End
2004-03-31
Support Year
17
Fiscal Year
2003
Total Cost
$308,020
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Carbonaro, Denise A; Jin, Xiangyang; Cotoi, Daniel et al. (2008) Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion. Blood 111:5745-54
Mi, Tiejuan; Abbasi, Shahrzad; Zhang, Hong et al. (2008) Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest 118:1491-501
Mohsenin, Amir; Mi, Tiejuan; Xia, Yang et al. (2007) Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice. Am J Physiol Lung Cell Mol Physiol 293:L753-61
Schaubach, B M; Wen, H Y; Kellems, R E (2006) Regulation of murine Ada gene expression in the placenta by transcription factor RUNX1. Placenta 27:269-77
Carbonaro, Denise A; Jin, Xiangyang; Petersen, Denise et al. (2006) In vivo transduction by intravenous injection of a lentiviral vector expressing human ADA into neonatal ADA gene knockout mice: a novel form of enzyme replacement therapy for ADA deficiency. Mol Ther 13:1110-20
Chunn, Janci L; Mohsenin, Amir; Young, Hays W J et al. (2006) Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol 290:L579-87
Chunn, Janci L; Molina, Jose G; Mi, Tiejuan et al. (2005) Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice. J Immunol 175:1937-46
Blackburn, Michael R; Kellems, Rodney E (2005) Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol 86:1-41
Aldrich, Melissa B; Chen, Wilma; Blackburn, Michael R et al. (2003) Impaired germinal center maturation in adenosine deaminase deficiency. J Immunol 171:5562-70
Morales, Julio C; Xia, Zhenfang; Lu, Tao et al. (2003) Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability. J Biol Chem 278:14971-7

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