Shivendra D. Shukla, PhD
Margaret Proctor Mulligan Professor
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)
- PhD in 1977, University of Liverpool (England)
- Postdoctoral research, University of Birmingham (England) 1977-80
- Research Assistant Professor, University of Texas Health Sciences Center, 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 of Excellence in Medical Education, MU, 1999
- Awarded ‘Order of Socrates II’ for contribution to Medical Education, MU, 2008
- Editorial Board Member: J. Pharm. Exp. Ther; World J. Hepatology; World J. Gastroenterology; Alcohol Research: Current Reviews
- Editor of Book: Platelet Activating Factor Receptor
- Service as regular member on NIH grant review panels
- Research supported by American Heart Association and National Institutes of Health
- Margaret Proctor Mulligan Endowed Professor in Medical Research, MU
- James, T, Aroor AR, Lim RW and Shukla SD. Histone H3 phosphorylation (S10, S28) and phosphoacetylation (K9/S10) are differentially associated with gene expression in liver of rats treated in vivo with acute ethanol. J. Pharm. & Exp. Ther. 340, 237-247, 2012.
- Park P, Lim, RW and Shukla SD. Gene selective histone H3 acetylation in the absence of increase in global histone acetylation in liver of rats chronically fed alcohol. Alcohol & Alcoholism 47, 233-239, 2012.
- Aroor AR, Jackson DE and Shukla SD. Dysregulated phosphorylation and nuclear translocation of cyclic-AMP response element binding protein (CREB) in rat liver after chronic ethanol binge. Eur J. Pharm. 679, 101-108, 2012.
- Aroor AR, Lowery J Roy, Restrepo RJ, Mooney BP and Shukla SD. A proteomic analysis of liver after ethanol binge in chronically ethanol treated rats. Proteome Science 10:29, 1-12, 2012.
- Shukla SD and Lim RW. Epigenetic effects of ethanol on the liver and gastrointestinal system, Alcohol Research: Current Reviews, 35(1), 47-55, 2013.
- Aroor AR, Restrepo RJ, Kharbanda, KK, and Shukla SD, Epigenetic histone modifications in a clinically relevant rat model of chronic-binge-mediated liver injury. Hepatology International. 8(2), 421-430, 2014
- Shukla SD, Restrepo RJ, Fish P, Lim RW and Ibdah JA. Different mechanisms for histone acetylation by ethanol and its metabolite acetate in rat primary hepatocytes. J. Pharm & Exp Ther 354, 18-23, 2015.
- Shukla SD, Aroor AR, Restrepo R, Kharbanda KK and Ibdah JA. In vivo acute on chronic ethanol effects in liver: A mouse model exhibiting exacerbated injury, altered metabolic & epigenetic responses. Biomolecules, 5, 3280-3294, 2015.
- Szary N, Rector RS, Uptergrove GM, Ridenhour S, Shukla SD, Thyfault JP, Koch LG, Britton SL and Ibdah JA. High intrinsic aerobic capacity protects against ethanol-induced hepatic injury and metabolic dysfunction: study using inbred high capacity runner rat model. Biomolecules 5, 3295-3308, 2015.
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.