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Ishwar S Singh
 

Ishwar S Singh Ph.D.

Academic Title: Assistant Professor
Primary Appointment: Medicine
isingh@umaryland.edu
Location: HSF 2 Room S311
Phone: (410) 605-5507
Fax: (410) 706-8162

Research Interests:

Current Research Interests:

• The role of fever and heat shock on cytokine/chemokine gene expression.
• The overlap and sharing of molecular mediators and signaling pathways between fever and the stress response.
• Phosphorylation and protein-protein interactions of the stress activated transcription factor heat shock factor 1 during fever.

Fever is a systemic response to infection and injury whereas heat shock, a cellular response, is a highly conserved and exquisitely regulated response against stress.  From an evolutionary perspective the heat shock response is highly conserved and is a very ancient response, with evidences present in archebacteria and eubacteria to higher eukaryotes.  In comparison, fever seems to be a more recently evolved process; an additional response to infection and injury in higher animals.

Although fever and heat shock are two distinct responses, they appear to be partially overlapping processes and share certain common signaling pathways, exemplifying how a more recently evolved response might exploit preexisting biochemical pathways for a new function.  One common thread between the two responses is the role of heat shock factor-1 (HSF-1), a transcription factor that is essential for generating the heat shock response.  We have found that HSF-1 is activated at febrile temperatures and acts as a repressor of tumor necrosis factor-alpha gene expression.  Other studies have shown that HSF-1 also represses interleukin 1beta and c-fos gene expression, which seem to suggest that HSF-1 may have a more diverse role than being just a stress activated transcriptional activator.

We propose that HSF-1 is an integral part of host defense against stress and inflammation and injury. Our studies are directed towards understanding the role of HSF-1 during fever and heat shock and how it regulates the expression of cytokine and chemokine genes. We are also focusing on the signaling cascades that are activated at febrile temperatures and whether these pathways lead to HSF-1 phosphorylation/dephosphorylation during fever. Another area we are presently interested in is the protein-protein interactions of HSF-1 during fever. In collaboration with Dr. Hasday’s laboratory we have developed a research program that is optimistically addressing the above questions using a unique combination of biochemical and molecular techniques, proteomics approaches and transgenic animals.


Publications:

Singh IS, Chatterjee TK, Ghosh JJ. (1983). Modification of morphine antinociceptive response by blood glucose status: Possible involvement of cellular energetics. Eur. J.  Pharmacol. 90,  437-439.

Singh IS, Ghosh JJ. (1984). Oxygen radicals and cell damage., The Lancet,  II ; 577.

Singh IS, Ghosh JJ. (1985). Serum Sorbitol Dehydrogenase: a suitable indicator for monitoring the severity of endotoxic shock. IRCS Med. Sci. 13,  362-363.

Hossain MA, Singh IS, Makar TK, Goswami S, Ghosh JJ. (1987). Discontinuation effects of oxazepam and diazepam treatment on brain GABA metabolism Neurochem. Int. 11,  49-55.

Makar TK, Singh IS, Basu MK, Ghosh JJ. (1988). Withdrawal effects of haloperidol, thioridazine, and clozapine on rat striatal membrane.  Med. Sci. Res. 16 ,  1115-1116.

Goswami S, Singh IS, Ghosh JJ. (1991).  Effect of pre- and post- treatments with diazepam on the rat brain GABAergic system during anoxic stress and recovery.  Neurochem. Int. 18 107-112.

Singh IS, Luo ZJ, Eng A, Erlichman J. (1991).  Molecular cloning and characterization of the promoter region of  the mouse regulatory subunit RII beta of Type II cAMP Dependent Protein Kinase. Biochem. Biophy. Res. Comm. 178,  221-226.

Luo Z, Singh IS, Fujihira T, Erlichman J. (1992).  Characterization of a minimal promoter element required for transcription of the mouse type II beta regulatory subunit of cAMP Dependent Protein Kinase J. Biol. Chem.  267;  24738-24747.

Singh IS, Luo Z, Kozlowski MT, Erlichman J. (1994).  Association of USF and c-Myc with a helix-loop-helix consensus motif in the core promoter of the murine type II beta regulatory subunit gene of cAMP Dependent Protein Kinase.  Mol. Endocrinol. 8;  1163-1174.

Mei X, Singh IS, Erlichman J, Orr GA. (1997).  Characterization of a Testis-specific, developmentally regulated  A-Kinase Anchor Protein present on the fibrous sheath of rat sperm.  Eur. J. Biochemistry 246:  425-432.

Jiang Q, DeTolla L, van Rooijen N, Singh IS, Fitzgerald B, Lipsky MM, Kane AS, Cross AS, Hasday JD.  (1999)  Febrile-range temperature modifies early systemic tumor necrosis factor alpha expression in mice challenged with bacterial endotoxin. Infect Immun. 67: 1539-46.

Jiang Q, Detolla L, Singh IS, Gatdula L, Fitzgerald B, van Rooijen N, Cross AS, Hasday JD. (1999)  Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxin-challenged mice. Am J Physiol. 276: R1653-1660.

Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi RM, Hasday JD.  (2000)  Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 68: 1265-1270.

Singh IS, Viscardi RM, Kalvakolanu I, Calderwood S, Hasday JD.  (2000)  Inhibition of tumor necrosis factor-alpha transcription in macrophages exposed to febrile range temperature. A possible role for heat shock factor-1 as a negative transcriptional regulator. J Biol Chem. 275: 9841-9848.

Fairchild KD, Viscardi RM, Hester L, Singh IS, Hasday JD. (2000) Effect of hypothermia and hyperthermia on cytokine production by cultured human mononuclear phagocytes from adults and newborns. J. Interferon Cytokine Res. 20, 1049-55.

Hasday JD and Singh IS. (2000)  Fever and the stress response: Distinct, partially overlapping processes. Cell Stress Chaperones 5, 471-80.

Hasday JD, Bannerman D, Sakarya S, Singh IS, Howard D, Drysdale B-E, Goldblum SE. (2001) Exposure to febrile temperature modifies endothelial cell response to tumor necrosis factor-¿.  J. Appl. Physiol 90, 90-98.

Wright G, Singh IS, Hasday JD, Farrance IK, Hall G, Cross AS, Rogers TB. (2002) Endotoxin stress-response in cardiomyocytes: NFkappaB activation and tumor necrosis factor-alpha expression. Am. J. Physiol Heart Circ Physiol 282: H872-H879.

Singh IS, He J-R, Calderwood S, Hasday JD. (2002) A high affinity HSF-1 binding site in the 5'-untranslated region of the murine TNF gene is a transcriptional repressor. J. Biol. Chem. 277: 4981-4988.

Chandrasekar B, Melby PC, Sarau HM, Raveendran M, Perla RP, Marelli-Berg F, Dulin NO, Singh IS. (2003) Chemokine-Cytokine crosstalk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a PI3 kinase-NF-kappa B pathway. J. Biol. Chem. 278: 4675-86.

Hasday JD, Garrison A, Singh IS, Standiford T, Ellis GS, Rao S, He JR, Rice P, Frank M, Goldblum SE, Viscardi RM. (2003) Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity. Am J Pathol.;162: 2005-17.

Atamas SP, Luzina IG, Choi J, Tsymbalyuk N, Carbonetti NH, Singh IS, Trojanowska M, Jimenez SA, White B. (2003) Pulmonary and Activation-Regulated Chemokine Stimulates Collagen Production in Lung Fibroblasts. Am J Respir Cell Mol Biol. 29: 743-9.

Singh IS, He J-R, Hester L, Fenton MJ and Hasday JD. (2004) Bacterial endotoxin modifies heat shock factor-1 activity in RAW 264.7 cells: Implications for TNF¿ regulation during exposure to febrile range temperatures. J. Endotoxin Res. 10: 175-184.

Fairchild KD, Singh IS, Patel S, Drysdale BE, Viscardi RM, Hester L, Lazusky HM, Hasday JD.  (2004) Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. Am J Physiol Cell Physiol. 287:C422-31.

Rice P, Martin E, He J-R, Frank M, DeTolla L, Hester L, O’Neill T, Manka C, Singh IS, Hasday JD (2004) Febrile-range Hyperthermia Augments Neutrophil Accumulation and Enhances Lung Injury in Experimental Gram-negative Bacterial Pneumonia. J Immunol. 15  3676-85.

Ellis GS, Carlson DE, Hester L, He JR, Bagby GJ, Singh IS, Hasday JD. (2005) G-CSF, but not corticosterone, mediates circulating neutrophilia induced by febrile-range hyperthermia. J Appl Physiol. 98:1799-804.

Fairchild KD, Singh IS, Carter HC, Hester L, Hasday JD. (2005) Hypothermia enhances phosphorylation of I kappa B kinase andprolongs nuclear localization of NF-kappa B in LPS-activated macrophages. Am J Physiol Cell Physiol. 289: C1114-21.

Hall G, Singh IS, Hester L, Hasday JD, Rogers TB. (2005) Inhibitor-{kappa}B Kinase-{beta}regulates LPS-induced TNF{alpha}production in cardiac myocytes through NF-{kappa}B p65 subunit phosphorylation. Am J Physiol Heart Circ Physiol. 289: H2103-11.

Nagarsekar A, Hasday JD, Singh IS. (2005) CXC Chemokines: A new family of Heat-shock proteins? Immunol Invest. 34: 381-98.

Kuwahara,I, Lillehoj EP, Lu W, Singh IS, Isohama Y, Miyata T, Chul Kim KC (2006) Neutrophil Elastase Induces IL-8 Gene Transcription and Protein Release Through p38/NF-κB Activation via EGFR Transactivation (COMMUNICATED)

Book chapter

Neurochemical changes in striatal membrane as markers for studying antipsychotic drug withdrawal.  Makar T, Singh IS, Ghosh JJ. Biomembranes in Health and Diseases, vol II; 445, (1991), Krieger Publishing, USA.

Presentations and Abstracts
Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Hasday JD, Jiang Q, Cross AS, Singh IS, Chen TT, Viscardi, RM. (Poster presentation) May 2000 American Thoracic Society International Conference, Toronto, Ontario, Canada.

TNF¿ transcription is inhibited in macrophages exposed to febrile range temperatures: A possible role for heat shock factor-1. Singh IS, Calderwood S, Viscardi RM, Hasday JD. (Poster presentation) May 2000 American Thoracic Society International Conference, Toronto, Ontario, Canada.

Febrile range temperatures may attenuate TNF¿ expression by interfering with NF¿B-dependent transcriptional activation. Singh IS, Cummings R, Viscardi RM, Hasday JD. (Poster presentation) May 2000 American Thoracic Society International Conference, Toronto, Ontario, Canada.
 
A high affinity HSF-1 binding site in the 5’-untranslated region of the murine TNF¿ gene is a transcriptional repressor. Singh IS, Calderwood S, He J-R, Hasday JD (Poster presentation) December 2001, Annual Meeting of American Society for Cell Biology, Washington, DC.

Differential phosphorylation of heat shock factor-1 at heat shock and febrile range temperature. Singh IS, Patel, He J-R, Hasday JD. (Poster presentation) December 2002, Annual Meeting of American Society for Cell Biology, San Francisco, CA.

Differential processing of HSF-1 and regulation of TNF¿ expression at febrile range temperatures. Singh IS, He J-R, Hester L, Hasday JD (invited oral presentation) September 2003, International Congress on Stress Responses in Biology and Medicine, Quebec City, Quebec, Canada.

Bacterial endotoxin modifies heat shock factor-1 activity in RAW 264.7 cells: Implications for TNF¿ regulation during exposure to febrile range temperatures. Singh IS, He J-R, Hester L, Hasday JD (oral presentation) May 2004, American Thoracic Society International Conference, Orlando, Florida.

Regulation of Interleukin-8 Expression by Heat Shock. Singh IS, Nagarsekar A, Manka C, He J-R, Hester L, Hasday JD. (Poster) December 2004, Annual Meeting of American Society for Cell Biology, Washington, DC.

CXC chemokines: A new family of heat-shock proteins? Singh IS, Nagarsekar A, He J-R, Hester L, Hasday JD (Poster). Gordon Research Conference 2005, Salve Regina University, Newport, RI.

Regulation of Interleukin-8 Expression by Heat Shock. Singh IS, Nagarsekar A, He J-R, Hester L, Hasday JD.  (Oral Presentation) Second International Congress On Stress Responses in Biology and Medicine 24th – 28th September 2005, Tomar (Hotel dos Templários), Portugal.

Differential responsiveness to heat shock protein (HSP) induction following heat acclimation. McClung JP, Montain SJ, Sawka MN, He J-R, Hasday JD, Singh IS. (Poster) Experimental Biology 2006, April 1-5, 2006. Moscone Convention Center, San Francisco, CA.