 Michael HershfieldProfessor of Medicine and Professor of BiochemistryGenetic and biochemical studies of inherited diseases of purine metabolism.. Contact InformationOffice Number: (919) 684-4184 Fax: (919) 684-4168 e-mail msh@biochem.duke.edu Lab Location Room 418 Sands Building Mailing Address Room 418 Sands Building Box 3049, DUMC Durham, NC 27710 Education
Research Interests(See Figure 1) Our research is related to the genetics, pathogenesis, and therapy of inherited disorders of purine metabolism. Our main focus has been on combined immunodeficiency caused by deficiency of adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP). We have investigated pathogenesis by studying the metabolism and biochemical effects of the nucleoside substrates of ADA and PNP in Iymphoid cells and mutant lymphoid cell lines, and in knockout mice. We have identified or investigated several potential mechanisms for lymphocyte depletion, including 1) inactivation of S-adenosylhomocysteine (AdoHcy) hydrolase by 2’-deoxyadenosine (dAdo), which can result in inhibition of biologically important transmethylation reactions; 2) expansion of the pools of dATP (in ADA deficiency) and dGTP (in PNP deficiency), resulting in inhibiiton of DNA replication/repair, triggering apoptosis; and 3) ADA binding to a cell membrane-associated glycoprotein known as CD26/dipeptidyl peptidase IV, which has been postulated to play a role in regulating thymocyte proliferation and the response of T lymphocytes to antigen. We have identified many of the mutations responsible for ADA deficiency. We are interested in the relationship between genotype and metabolic and clinical phenotype, and in the effects of mutations on ADA gene expression and ADA folding. We helped to develop enzyme replacement therapy for ADA deficiency with polyethylene glycol-modified ADA (PEG-ADA), and we are interested in the potential for treating other purine metabolic disorders with PEG-enzymes. Lab MembersRecent Publications1. Arredondo-Vega FX, Santisteban I, Richard E, Bali P, Koleilat M, Loubser M, Al-Ghonaium A, Al-Helali M, Hershfield MS: Adenosine deaminase deficiency with mosaicism for a second-site suppressor of a splicing mutation: Decline in revertant T lymphocytes during enzyme replacement therapy. Blood 2002, 99:1005-10132. More… 2. Richard E, Alam SM, Arredondo-Vega FX, Patel DD, Hershfield MS: Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/Dipeptidyl peptidase IV. J Biol Chem 2002, 277:1720-1726 More… 3. Ariga T, Oda N, Santisteban I, Arredondo-Vega FX, Shioda M, Ueno H, Terada K, Kobayashi K, Hershfield MS, Sakiyama Y: Molecular basis for paradoxical carriers of adenosine deaminase (ADA) deficiency who show extremely low level of ADA activity in peripheral blood cells without immunodeficiency. J Immunol, 2001,166:1698-1702. More… 4. Kelly SJ, Delnomdedieu M, Oliverio MI, Williams LD, Saifer MGP, Sherman MR, Coffman TM, Johnson GA, Hershfield MS: Diabetes insipidus in urate oxidase deficienct mice: a model for evaluating therapy with poly(ethylene glycol)-uricase. J Am Soc Nephrol, 2001, 12:1001-1009. More… 5. Hershfield MS, Mitchell BS: Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency, in: Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001, pp2585-2625. More… 6. Arpaia E, Benveniste P, Di Cristofano A, Gu Y, Dalal I, Kelly S, Hershfield M, Pandolfi PP, Roifman CM, Cohen A: Mitochondrial basis for immune deficiency: Evidence from purine nucleoside phosphorylase-deficient mice. J Exp Med 2000;191:2197-2207. More… 7. Blackburn MR, Aldrich M, Volmer JB, Chen W, Zhong H, Kelly S, Hershfield MS, Datta SK, Kellems RE. The use of enzyme therapy to regulate the metabolic and phenotypic consequences of adenosine deaminase deficiency in mice. Differential impact of pulmonary and immunologic abnormalities. J Biol Chem. 2000; 275:32114-21. More… 8. Thompson LF, Van De Wiele CJ, Laurent AB, Hooker SW, Jiang H, Khare K, Kellems RE, Blackburn MR, Hershfield MS, Resta R. Thymopoiesis is inhibited by metabolites from apoptotic thymocytes in adenosine deaminase deficient murine fetal thymic organ cultures. J Clin Invest, 2000, 106:1149-1157. More… 9. Richard E, Arredondo-Vega FX, Santisteban I, Kelly SJ, Patel DD, Hershfield MS: The binding site of human adenosine deaminase for CD26/dipeptidyl peptidase IV: The Arg142Gln mutation impairs binding to CD26 but does not cause immune deficiency. J Exp Med 2000; 192:1223-35. More… 10. Kohn DB, Hershfield MS, Carbonaro D, Shigeoka A, Brooks J, Smogorzewska EM, Barsky LW, Chan R, Burotto F, Annett G, Nolta JA, Crooks G, Kapoor N, Elder M, Wara D, Bowen T, Madsen E, Snyder FF, Bastian J, Muul L, Blaese RM, Weinberg K, Parkman R: T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA- deficient SCID neonates. Nat Med 1998; 4:775-780. More… 11. Turner MA, Yuan CS, Borchardt RT, Hershfield MS, Smith GD, Howell PL. Structure determination of selenomethionyl S-adenosylhomocysteine hydrolase using data at a single wavelength. Nat Struct Biol 1998; 5:369-76. More… 12. Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet. 1998; 63:1049-59. More… |
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