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Ralph C. Nichols, Ph.D.

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Since 1979, Dr Nichols has studied mechanisms of the inflammatory response and the genetics of disease. In research at George Washington University, Dr. Nichols characterized a cell membrane pool of arachidonic acid, a precursor of multiple inflammatory mediators, and showed that this molecule was in much higher abundance than previously known. Later, at the NIH, Dr. Nichols cloned and characterized RNA-binding proteins recognized by autoantibodies in the inflammatory autoimmune disease polymyositis/dermatomyositis (PM/DM). Included in this study of RNA biology was the development of a method for expression and purification of the major PM/DM autoantigen, histidyl-tRNA-synthetase, work that resulted in a patent award to the NIH research group that included Dr. Nichols. Also while at the NIH, Dr Nichols conducted genetic studies of patients suffering from muscle-specific diseases that masquerade as PM/DM. Analysis of targeted muscle-specific genes revealed that patients suffered not from autoimmune disease, but from genetic defects in the glucose-handling enzymes, phosphofructokinase (PFK) and acid maltase (AM). Further research led to the discovery of alternative messenger RNA (mRNA) splice variants in patients that resulted in PFK deficiency and AM deficiency.

Since coming to Dartmouth, Dr. Nichols has continued his studies on RNA biology and on RNA-binding proteins, with special focus on trans-acting regulatory proteins that bind cis elements in disease-related messenger RNA. Work includes analysis of how the RNA-binding protein hnRNA-A2 shuttles between the cytoplasm and the nucleus of the cell. One domain of the hnRNP-A2 protein was identified that controls localization of the protein to the nucleus. Using site-directed mutagenesis and structure-function analysis, the candidate domain was removed and the hnRNP-A2 mutant localized to the cytoplasm, demonstrating that this protein may be critical to mRNA transport. In related work, Dr. Nichols has shown that while in the cytoplasm hnRNP-A2 decreases the stability of targeted mRNA's. This regulatory effect acts on the crucial glucose transporter molecule GLUT1 (glucose transporter-1) because when the cytoplasmic hnRNP-A2 mutant is expressed in cells levels of GLUT1 protein are decreased. This research effort contributes to our understanding of the mechanisms of molecular movement in the cell and sheds light on how the stability of the mRNA of critical disease genes is controlled by shuttling mRNA-binding proteins. This and other research led to the award of a Merit Review grant from the Veterans Administration.
Other recent research in Dr. Nichols laboratory has focused on regulation of two essential growth factors, VEGF (vascular endothelial growth factor) and TNF-alpha (tumor necrosis factor). Of major importance in many diseases, VEGF is up-regulated in cancer and down-regulated in tissue under oxidative stress (hypoxia and anoxia), as is found in heart attacks and stroke. Hence, both over- and under-expression of the VEGF molecule is critical to disease. To characterize the regulatory machinery acting on the VEGF mRNA 3'-untranslated region (3'-UTR) Dr Nichols' group has been awarded a grant from the Arthritis Institute (NIAMS/NIH). Understanding which regions of the VEGF mRNA molecule are important, and understanding which mRNA-binding proteins act on the VEGF mRNA will provide novel insight into the mechanism of disease progression and open new avenues of research to find a cure for mis-regulated expression of growth factors. New work includes studies of post-transcriptional regulation of P450 enzymes (Cyp-2A5, CYP-3A4, CYP-1A2), especially in toxicological models including low-dose arsenic effects on human cancer.