Shivendra D. Shukla, Ph.D.
Research Interests
[A] Epigenetic and cell signaling effects of ethanol on liver: The effect of ethanol on cell signaling in liver cells (hepatocytes) is being investigated with the goal to identify the key steps altered by ethanol in (a) MAP kinase pathway and (b) in the nuclear responses. Proteomic analysis of the kinase substrates affected by ethanol is one of the issues being addressed. In the nuclear effects, the focus is on the chromatin histone modification(s) and the goal is to understand the molecular mechanism and transcriptional consequence of ethanol induced epigenetic histone modifications (i.e. acetylation, methylation and phosphorylation). The CHIP assay, gene and protein array technologies are being utilized to identify the ethanol affected genes and proteins relevant to alcoholic liver disease. The laboratory also uses pharmacological agents in animals/ in vivo for translational implications of these studies.
[B] Platelets and vascular remodelling: The role of blood platelets and its secretory products in vascular responses is another topic of focus. We have established the pharmacological properties of platelet activating factor (PAF) and its receptor associated cell signaling responses in human and rabbit platelets. Our new observations show that upon activation, human platelets secrete specific PKC isozymes (PKC α, βII and δ). This raises the question of extracellular role of these PKCs on adjacent cells (eg. endothelial or smooth muscle cells) in the vasculature or at the site of injury where platelets adhere and secrete these isozymes. Diabetic platelets, which exhibit hypersensitivity, are being used to test whether secretion of these PKC’s have significance in the thromboembolic complications observed in diabetics.
Working model (Microsoft Powerpoint .ppt)
Professional Background
- PhD in 1977 from the University of Liverpool (England)
- Postdoctoral work at the University of Birmingham (England) 1977-1980
- Research Assistant Professor ,University of Texas Health Sciences Center in San Antonio, Texas 1980-84
- Assistant Professor to Professor, MU 1984-present
- Recipient of NIH Research Career Development Award 1989-1994
- Director of Graduate Studies in Pharmacology, MU 1989-1999
- Award for Excellence in Medical Education, 1999
- Awarded ‘Order of Socrates II’ for contribution to Medical Eeducation, 2008
- Editorial Board Member: J. Pharm. Exp. Ther.; World J. Gastroenterology
- Editor of Book : Platelet Activating Factor Receptor
- Service on several NIH review panels; current regular member of NIH study section (AA1)
- Research supported by grants from the National Institues of Health
- Margaret Proctor Mulligan Endowed Professor in Medical Research
Selected Publications
- Park, P., Lim, R.W. and Shukla, S.D. Involvement of histone acetyltransferase (HAT) in ethanol induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression. Am. J. Physiol.289, G 1124-G1136, 2005.
- Kim, J. and Shukla S.D. Acute in vivo effect of ethanol (binge drinking) on histone H3 modifications in rat tissues. Alcohol & Alcoholism 41, 126-132, 2006.
- Park, P, Aroor A. and Shukla S.D. Role of Ras in ethanol modulation of angiotensin II activated p42/44 MAP Kinase in rat hepatocytes, Life Sciences, 79, 2357-2363, 2006.
- Shukla, S.D. and Aroor, A.R. (Editorial) Epigenetic effects of ethanol in liver and GI injury. World J. Gastroenterology. 12, 5265-5271, 2006.
- Lee, Y and Shukla, S.D. Histone H3-Serine -10 & -28 phosphorylation by ethanol and acetaldehyde in hepatocytes is mediated by p38MAPKinase. Eur. J. Pharm. 573, 29-38, 2007.
- Bhadra, M., Bhadra, U., Jackson, D.E., Mamatha, L., Park, P. and Shukla, S.D. Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up-& down-regulation of genes by ethanol in hepatocytes. Life Sciences 81, 979-987, 2007.
- Choudhury, M and Shukla S.D. Surrogate alcohols modify histone H3 acetylation via histone acetyl transferase and also sensitize ethanol induced acetylation in rat hepatocytes. Alcoholism: Clinical & Exp. Res. 32, 1-11, 2008.
- Weng, Y, Aroor, A and Shukla S.D. Ethanol inhibition of Angiotensin II stimulated Tyr-705 and Ser-727 STAT3 phosphorylation in cultured rat hepatocytes: Relevance to activation of p42/44 MAP Kinase. Alcohol 42, 397-406, 2008.
- Shukla, SD, Kansra, SV, Reddy, MA, Shukla, SM, Klachko DM and Sturek M. Diabetic pig platelets exhibit hypersensitivity to thrombin. Comparative Medicine. 58, 481-484, 2008.
- shukla, SD, Velazquez, J, French, SW, Lu, SC, Ticju, MK ans Zakhari S. (Review) Emerging role of epigenetics in the actions of alcohol. Alcoholism: Clin & Exp. Res. Vol 32, 1525-1534. 2008.
Methodology/Techniques
The laboratory uses a variety of methods including: liver perfusion; cell culture; in vivo animal studies; receptor binding; cell signaling; protein kinase assays; post-translational histone modifications; blood platelet aggregation; western blotting; immuno-fluorescence detection, confocal microscopy; real time PCR; functional-proteomics; CHIP assay; gene and protein arrays, transcription assays, and various other pharmacological techniques.
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