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Project 2

Lipid peroxidation and aging in invertebrate models

 

 

 

Piotr Zimniak, Ph.D.

Professor

Department of Pharmacology and Toxicology

        

 

Research interests:

 


 

Principal Investigator/Program Director (Last, First, Middle):

 

 

BIOGRAPHICAL SKETCH

Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person.  DO NOT EXCEED FOUR PAGES.

 

NAME

Piotr Zimniak

POSITION TITLE

Professor of Pharmacology and Toxicology

eRA COMMONS USER NAME

PZIMNIAK

EDUCATION/TRAINING  (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)

INSTITUTION AND LOCATION

DEGREE

(if applicable)

YEAR(s)

FIELD OF STUDY

Univ. of Vienna, Vienna, Austria

B.S. equiv..

1970

Chemistry

Univ. of Vienna, Vienna, Austria

PhD

1975

Biochemistry

Cornell Univ., Ithaca, NY

Post-doc

1978

Membranes and transport

Baylor College of Medicine

Post-doc

1981

Membranes and transport

 

 

 

 


 

A.        POSITIONS AND HONORS

 

Professional Experience

1981-1985         Assistant Prof., Dept. Biochem. and Pharmacol., Tufts Univ. Sch. Med., Boston, MA

1985-1988         Assistant Prof., Dept. Int. Med., Univ. of Texas Med. Sch., Houston, TX

1988-1988         Joint appt. as Assist. Prof., Dept. Bioch. and Molec. Biol., Univ. of Texas Med. Sch., Houston, TX

1988-1989         Assistant Prof., Dept. of Med., Univ. of Rochester Sch. Med., Rochester, NY

1989-1989         Visiting Prof., Biocenter of the Univ. Basel, Switzerland

1989-1997         Associate Prof., Dept. Int. Med., Univ. of Arkansas Med. Sci., Little Rock, AR

1991-1997         Joint appt. as Assoc. Prof., Dept. Bioch. and Molec. Biol., Univ. of Ark. Med. Sci., Little Rock, AR

1997-2002         Professor, Dept. of Int. Med., and Dept. of Bioch. and Molec. Biol., Univ. of Ark. Med. Sci., Little Rock, AR

2002-present     Professor, Dept. Pharm./Tox., and Depts. Bioch. & Mol. Biol., and Int. Med.., Univ. of Ark. Med. Sci.

 

Professional Organizations

1982-present     American Society of Biochemistry and Molecular Biology

1982-present     New York Academy of Sciences

1985-present     American Chemical Society

1986-present     American Association for the Advancement of Science

 

Study Section Membership

1996-2000         NIH ALTX-1 Study Section (ad hoc 1996-97, permanent from fall 1997-summer 2000)

1996-2000         VA Gastroenterology Merit Review Board (ad hoc 1996-97; permanent 1997-2000)

June 2003         Member of NIH Review Panel for RFA entitled "Comparative Biology: Mechanisms of Aging", NIA.

Dec. 2003         Member of NIH NIA Review Panel for a Program Project grant.

Nov. 2004         Ad hoc member of NIH CICS (Clinical and Integrative Cardiovascular Science) Study Section.

 

B.        SELECTED PEER-REVIEWED PUBLICATIONS (OUT OF 140)

Cheng K, Chen Y, Zimniak P, Raufman J-P, Xiao Y, Frucht H. Functional interaction of lithocholic acid conjugates with M3 muscarinic receptors on a human colon cancer cell line. Biochim. Biophys. Acta 1588(1): 48-55, 2002.

Yang Y, Sharma R, Zimniak P, Awasthi YC. Role of a class glutathione S-transferases as antioxidant enzymes in rodent tissues. Toxicol. Appl. Pharmacol. 182: 105-115, 2002.

Singh SP, Janecki AJ, Srivastava SK, Awasthi S, Awasthi YC, Xia SJ, Zimniak P. Membrane association of glutathione S-transferase mGSTA4-4, an enzyme that metabolizes lipid peroxidation products. J. Biol. Chem. 277: 4232, 2002.

Sharma R, Sharma A, Yang Y, Awasthi S, Singhal SS, Zimniak P, Awasthi YC. Functional reconstitution of Ral-binding GTPase activating protein, RLIP76, in proteoliposomes catalyzing ATP-dependent transport of glutathione conjugate of 4-hydroxynonenal. Acta Biochim. Pol. 49: 693-701, 2002.

Guo J, Zimniak L, Zimniak P, Orchard JL, Singh SV. Cloning and expression of a novel Mu class murine glutathione transferase isoenzyme. Biochem. J.366: 817-824, 2002.

Cheng KR, Khurana S, Chen Y, Kennedy RH, Zimniak P, Raufman JP. Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. J. Pharm. Expt. Ther. 303: 29-35, 2002.

Awasthi S, Sharma R, Singhal SS, Zimniak P, Awasthi YC. RLIP76, a novel transporter catalyzing ATP-dependent efflux of xenobiotics. Drug Metabol. Disp. 30: 1300-1310, 2002.

Awasthi S, Sharma R, Yang YS, Singhal SS, Pikula S, Bandorowicz-Pikula J, Singh SV, Zimniak P, Awasthi YC. Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76). Acta Biochim. Pol. 49: 855-867, 2002.

Bose C, Guo JX, Zimniak L, Srivastava SK, Singh SP, Zimniak P, Singh SV. Critical role of allyl groups, and disulfide chain in induction of Pi class glutathione transferase in mouse tissues in vivo by diallyl disulfide, a naturally occurring chemopreventive agent in garlic. Carcinogenesis 23: 1661-1665, 2002.

Raufman JP, Chen Y, Cheng KR, Compadre C, Compadre L, Zimniak P. Selective interaction of bile acids with muscarinic receptors: a case of molecular mimicry. Eur. J. Pharmacol. 457: 77-84, 2002.

Sawicki R, Singh SP, Mondal AK, Benes H, Zimniak P. Cloning, expression, and biochemical characterization of one Epsilon-class (GST-3) and ten Delta-class (GST-1) glutathione S-transferases from Drosophila melanogaster, and identification of additional nine members of the Epsilon class. Biochem. J. 370: 661-669, 2003.

Awasthi S, Singhal SS, Sharma R, Zimniak P, Awasthi YC. Transport of glutathione-conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): a novel link between G-protein and tyrosine kinase signaling and drug resistance. Internat. J. Cancer 106: 635-646, 2003.

Singhal SS, Singhal J, Sharma R, Singh SV, Zimniak P, Awasthi YC, Awasthi S. Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. Int. J. Oncol. 22: 365-375, 2003.

Awasthi S, Singhal SS, Singhal J, Cheng J, Zimniak P, Awasthi YC. Role of RLIP76 in lung cancer doxorubicin resistance: II. Doxorubicin transport in lung cancer by RLIP76. Int. J. Oncol. 22: 713-720, 2003.

Awasthi S, Singhal SS, Singhal J, Yang Y, Zimniak P, Awasthi YC. Role of RLIP76 in lung cancer doxorubicin resistance: III. Anti-RLIP76 antibodies trigger apoptosis in lung cancer cells and synergistically increase doxorubicin cytotoxicity. Int. J. Oncol. 22: 721-732, 2003.

Raufman JP, Cheng K, Zimniak P. Activation of muscarinic receptor signaling by bile acids – physiological and medical implications. Dig. Dis. Sci. 48: 1431-1444, 2003.

Yang Y, Sharma A, Sharma R, Patrick B, Singhal SS, Zimniak P, Awasthi S, Awasthi YC. Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: Role of 4-hydroxynonenal in UVA mediated signaling for apoptosis. J. Biol. Chem. 278: 41380-41388, 2003.

Cheng KR, Zimniak P, Raufman JP. Transactivation of the epidermal growth factor receptor mediates cholinergic agonist-induced proliferation of H508 colon cancer cells. Cancer Res.63: 6744-6750, 2003.

Engle MR, Singh SP, Czernik PJ, Gaddy D, Montague DC, Ceci JD, Yang Y, Awasthi S, Awasthi YC, Zimniak P. Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4 hydroxynonenal: generation and analysis of mGsta4 null mouse. Toxicol. Appl. Pharmacol. 194: 296-308, 2004.

Yang Y, Yang Y, Trent MB, He N, Lick SD, Zimniak P, Awasthi YC, Boor PJ. Glutathione-S-transferase A 4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis. Atherosclerosis 173: 211-21, 2004.

Sharma R, Brown D, Awasthi S, Yang Y, Sharma A, Patrick B, Saini MK, Singh SP, Zimniak P, Singh SV, Awasthi YC. Transfection with 4-hydroxynonenal metabolizing glutathione S-transferase isozymes leads to phenotypic transformation and immortalization of adherent cells. Eur. J. Bioch.271 1690-1701, 2004.

Singh SV, Varma V, Zimniak P, Srivastava SK, Marynowski SW, Desai D, Amin S, Ji X. Structural basis for catalytic differences between Alpha class human glutathione transferases hGSTA1-1 and hGSTA2-2 for glutathione conjugation of environmental carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide. Biochemistry 43: 9708-9715, 2004.

Wu Z, Minhas GS, Wen D, Jiang H, Chen K, Zimniak P, Zheng J. Design, synthesis, and structure-activity relationships of haloenol lactones: site-directed and isozyme-selective glutathione S-transferase inhibitors. J. Medicinal Chem. 47: 3282-3294, 2004.

Gu Y, Guo J, Pal A, Pan S-S, Zimniak P, Singh SV, Ji X.  Crystal structure of human glutathione S-transferase A3-3 and mechanistic implications for its high steroid isomerase activity. Biochemistry 43:15673-15679, 2004.

Singh SP, Chen T, Chen L, Mei N, McLain E, Samokyszyn V, Thaden JJ, Moore MM, Zimniak P. Mutagenic effects of 4-hydroxynonenal triacetate, a chemically protected form of the lipid peroxidation product 4-hydroxynonenal, as assayed in L5178Y Tk+/- mouse lymphoma cells. J. Pharm. Expt. Ther. 313: 855-861, 2005.

McEwen JE, Zimniak P, Mehta JL, Shmookler Reis RJ.  Molecular pathology of aging and its implications for senescent coronary atherosclerosis.  Curr. Opin. Cardiol. 20: 399-406, 2005

Patrick B, Li J, Jeyabal PVS, Reddy PMRV, Yang YS, Sharma R, Sinha M, Luxon B, Zimniak P, Awasthi S, Awasthi YC. Depletion of 4-hydroxynonenal in hGSTA4-transfected HLE B-3 cells results in profound changes in gene expression. Biochem. Biophys. Res. Commun. 334: 425–432, 2005.

Ayyadevara S, Engle MR, Singh SP, Dandapat A, Lichti CF, Benes H, Shmookler Reis RJ, Liebau E, Zimniak P. Life span and stress resistance of Caenorhabditis elegans are increased by expression of glutathione transferases capable of metabolizing the lipid peroxidation product 4-hydroxynonenal. Aging Cell 4: 257-271, 2005.

 

C.        RESEARCH SUPPORT

 

Ongoing research support

 

R01 AG 18845-01 (Zimniak, PI)

3/1/02 - 2/28/07

 

NIH/NIA

$250,000

 

Role of lipid peroxidation and 4-hydroxynonenal in aging

 

Major goals: To create transgenic Drosophila lines with inducible and tissue-specific expression of several mammalian GSTs, some of which have the ability to conjugate 4-hydroxynonenal or to reduce lipid hydroperoxides. The lines will be used to evaluate, under normal and stressed conditions, the effects of 4-hydroxynonenal metabolism on biochemical markers of aging and on life span.

 

Role: PI

 

 

R01 ES 07804-06 (Zimniak, PI)

8/1/96 - 7/31/06

 

NIH/NIEHS

$250,000

 

Glutathione transferases and oxidative stress toxicology

Major goals: To characterize the physiological role of 4-hydroxynonenal metabolism catalyzed by mGSTA4-4 in a knockout mouse lacking the enzyme, and in transfected cells. To continue structure-function relationship studies on mGSTA4-4.

Role: PI

 

R01 ES 09140 (S.V. Singh, PI  /  P.Zimniak, subcontract PI)

2002-2006

 

NIH/NIEHS

$72,792 subcontract direct costs

 

Toxicological relevance of human GST P1-1 polymorphism

Major goals: The application is based on our previous finding that allelic forms of hGSTP1-1 exhibit differential activity toward benzo[a]pyrene diol epoxide, a known cigarette smoke and environmental carcinogen, and similar PAHs.  Allelic forms of hGSTP1-1 will be characterized in knock-in mice and in transfected cells.

Role: Subcontract PI

 

R01 AG 18845S (Zimniak, PI)

3/1/02 - 2/28/07

 

NIH/NIA

$80,000

 

Murine transgenic models of genetic alterations attenuating metabolic damage and extending longevity in invertebrates (Supplement to: Role of lipid peroxidation and 4-hydroxynonenal in aging)

Major goals: To investigate whether genes whose mutations modulate life span in invertebrates have the same effect in mice.

Role: PI

 

 

 

Completed research support

 

no project number (Zimniak, PI)

10/1/92 - 9/31/04

 

VA

$194,900

 

Mechanisms of hepatic transport of organic anions

Major goals: To characterize biochemically and physiologically a novel ATP-dependent organic anion transporter of liver canalicular membranes.

Role: PI

 

Zimniak, PI

7/1/2004 - 6/30/2005

 

Arkansas Tobacco Settlement Fund

$24,300

 

Microarray analysis of differences between control and mGsta4 null mice

Major goals: To determine differences in gene expression patterns between control and mGsta4 null mice

Role: PI