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Nahum Duker, MD

 

Nahum Duker, MD

 

Professor, Pathology and Laboratory Medicine

Assistant Professor, Fels Institute for Cancer Research and Molecular Biology

Telephone:  215-707-3258

Fax:  215-707-2805

Email: granduke@temple.edu

 

Department of Pathology and Laboratory Medicine

Fels Institute for Cancer Research and Molecular Biology

 

Educational Background:

 

Undergraduate School          

University of Illinois

Chicago, Illinois

1959-62

 

Medical School

University of Illinois College of Medicine

Chicago, Illinois

1962-1966

 

Graduate Medical Education

Intern in Pathology

Bellevue Hospital

1966-1967

 

Residency, Pathology

New York University Medical Center

1970-1976

             

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Research Interests:

 

A paradigm for etiogenesis of neurodegenerative disorders has emerged which implicates unrepaired oxidative DNA damage in neuron cell death via apoptosis.  Evidence indicates unrepaired DNA purine dimers to be the molecular link between intracerebral deposition of amyloid-ß protein [Aß] and neural cell loss in Alzheimer's disease.  Aß reacts with the receptor for advanced glycation end products [RAGE], resulting in generation of free radicals; these result in oxidative DNA damages.  The RAGE receptor is present on the surfaces of neural and endothelial cells.  Over fifty such types of base damages have been described.  Most are monomeric, but a number of DNA dimers formed between adjacent purines have been synthesized in my laboratory.  One purine dimmer, 8-8-(2'-deoxy­guano­syl)-2'-deoxyguanosine-5'-mono­phosphate, was used as a hapten for elicitation of rabbit anti-purine dimer antiserum.  DNA oxidized by the Fenton reaction is bound by this antiserum.  Therefore, induction and excision of DNA purine dimers can be immunologically assayed.  Incubation of PC-12 cells, derived from the neural tumor pheochromocytoma, with Aß induces these purine dimers; these are subsequently removed from cellular DNA by the nucleotide excision repair pathway.  There are nucleotide excision repair defects in xeroderma pigmentosum, a human disease that results in neurodegeneration, with evidence for such defects in familial Alzheimer's disease and Down's syndrome.  To elucidate the Aß reaction with cells that result in DNA dam­age and possible apoptosis, a number of exploratory studies will be executed.  These include devising of a set of Aß-sensitive fibroblasts from these diseases by inducing stable expression of the cloned human RAGE gene.  The induction and excision of oxidized DNA bases, including 8-oxoguanine and but stressing ­purine dimers, resulting from Aß-induced, radiation-induced and chemical-induced oxidative DNA damages will be assayed in these cells.  To abet the assay, stable lines of cells producing monoclonal anti-DNA-purine-dimer antibodies will be constructed.  Modulation of proteins involved in excision-repair of these oxidative DNA damages during different phases of the cell cycle will be examined.  The effects of induction and excision of these oxidized DNA moieties on initiation of apoptosis will be assayed, and the progress of apoptosis and its vital checkpoints explored.  These in vitro studies will be extended in vivo by development of mouse strains with both increased Aß production and reduced DNA repair capacities.  This will allow for testing of the paradigm linking Aß, the congophilic angiopathy (with deposits of amyloid in intracerebral blood vessels) of Alzheimer’s disease, oxidative DNA damage and repair, with neural cell losses that result in the clinical and pathological changes characteristic of Alzheimer's disease and other conditions.  Therefore, these studies can result in elucidation of the roles of DNA intrastrand purine dimers in the etiogenesis of human neurodegenerative disorders.

 

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

11255222. Duker NJ, Sperling J, Soprano KJ, Druin DP, Davis A, Ashworth R, beta-Amyloid protein induces the formation of purine dimers in cellular DNA. J Cell Biochem 81:3(393-400)2001

10967552. Vairapandi M, Liebermann DA, Hoffman B, Duker NJ, Human DNA-demethylating activity: a glycosylase associated with RNA and PCNA. J Cell Biochem 79:2(249-60)2000 Aug 2

8806682. Vairapandi M, Duker NJ, Partial purification and characterization of human 5-methylcytosine-DNA glycosylase. Oncogene 13:5(933-8)1996 Sep 5

7521001. Vairapandi M, Duker NJ, Excision of ultraviolet-induced photoproducts of 5-methylcytosine from DNA. Mutat Res 315:2(85-94)1994 Sep

8265344. Vairapandi M, Duker NJ, Enzymic removal of 5-methylcytosine from DNA by a human DNA-glycosylase. Nucleic Acids Res 21:23(5323-7)1993 Nov 25

1383813. Ganguly T, Duker NJ, Inhibition of DNA polymerase activity by thymine hydrates. Mutat Res 293:1(71-7)1992 Nov

1379342. Ganguly T, Duker NJ, Reduced 5-hydroxymethyluracil-DNA glycosylase activity in Werner's syndrome cells. Mutat Res 275:2(87-96)1992 Mar

2062648. Ganguly T, Duker NJ, Stability of DNA thymine hydrates. Nucleic Acids Res 19:12(3319-23)1991 Jun 25

2207100. Ganguly T, Weems KM, Duker NJ, Ultraviolet-induced thymine hydrates in DNA are excised by bacterial and human DNA glycosylase activities. Biochemistry 29:31(7222-8)1990 Aug 7

2336388. Duker NJ, Weems KM, Excision of cytosine hydrates from Z-DNA. Nucleic Acids Res 18:8(2007-10)1990 Apr 25

2366800. Ganguly T, Duker NJ, Glycosylases that excise modified DNA pyrimidines in young and senescent human WI-38 fibroblasts. Mutat Res 237:2(107-15)1990 Mar

2308590. Ganguly T, Duker NJ, Differential cell cycle modulation of human DNA glycosylases against oxidized pyrimidines. Mutat Res 235:2(137-46)1990 Mar

2655693. Weiss RB, Gallagher PE, Brent TP, Duker NJ, Cytosine photoproduct-DNA glycosylase in Escherichia coli and cultured human cells. Biochemistry 28:4(1488-92)1989 Feb 21

2553050. Gallagher PE, Weiss RB, Brent TP, Duker NJ, A human endonuclease incises ultraviolet-irradiated DNA at cytosines and oxidized DNA at thymines. Mol Carcinog 2:4(188-91)1989

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