Dr. Singh

Ishwar S Singh Ishwar S. Singh, Ph.D.
Asstistant Professor of Medicine.

Department: Division
Medicine: Pulmonary and Critical Care Medicine

Special Interests: Transcriptional regulation and cytokine gene expression at febrile temperatures.
Ph.D.: Biochemistry, University of Calcutta, Kolkata, India.

Current Research Interests:

  • The role of fever and febrile range temperature on cytokine gene expression.
  • The overlap and sharing of molecular mediators and signaling pathways between febrile response and the stress response.

Fever is a complex physiologic response to infection and injury whereby a temporary resetting of the body's thermostatic set point occurs causing an increase in the core temperature. The heat shock response, on the other hand, is an essential, highly conserved and exquisitely regulated response against stresses including extremes of temperature, toxic chemicals and high levels of radiation. From an evolutionary perspective the heat shock response is highly conserved and 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. HSF-1 is present in the cell as a non DNA-binding monomer. Upon heat shock (or other stress) the protein is activated, that is, it trimerizes and undergoes phosphorylation to a DNA binding form recognizing a pentameric 'nGAAn' dyad repeat and transactivates the expression of heat shock protein genes. We have found that HSF-1 is also activated at febrile temperatures but acts as a repressor of tumor necrosis factor-alpha gene expression. Other people 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.

How inflammatory mediators generate a burst of proinflammatory cytokine production during fever? How does the cell recognize and quantitate stress, generate signals and transduce messages for an appropriate response? What dictates the role of the stress-activated transcription factor HSF-1 as an activator or a repressor? Is the information encrypted in the DNA sequences flanking the HSF-1 binding site or is it the protein itself? How do phosphorylation/dephosphorylation events and/or protein-protein interaction of HSF-1 regulate its role during febrile or heat shock temperatures? These are the few questions we are principally focusing on and pursuing very optimistically using biochemical and molecular techniques and transgenic animals.

Current Research Funding:

RO1 (07/01/2004 - 06/30/2008)
Role: PI

VA Merit (10/01/2004 - 09/30/2007)
Department of Veterans Affairs
Role: PI

RO1 (04/01/2004 - 03/31/2009)
Role: Co-investigator (PI, Jeffrey D. Hasday, MD)

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