Nuria Morral, Ph.D.
Associate Professor of Medical & Molecular Genetics
Associate Professor of Biochemistry & Molecular Biology
Member of the Center for Diabetes Research
975 West Walnut St, IB130
Indianapolis, IN 46202
- B.S., 1987, University of Barcelona, Spain
- PhD, 1993, University of Barcelona, Spain
- Post-doctoral, 1994-1998, Baylor College of Medicine, Houston, TX, and Mount Sinai School of Medicine, New York, NY
Type 2 diabetes mellitus is a metabolic disease characterized by elevated blood glucose concentration that results from inadequate insulin action in insulin-sensitive tissues and from abnormal insulin secretion. In the USA, Europe and most Western countries, type 2 diabetes affects 5-7% of the population. More than 80% of type 2 diabetes patients are overweight or obese and display several abnormalities in lipid metabolism, including hepatic steatosis. The liver is one of the most important tissues affected by fatty acid accumulation, where they induce abnormal insulin signal transduction, decrease insulin extraction, and increase triglyceride production and hepatic glucose output. Dr. Morral’s research is directed at understanding the molecular alterations induced by fatty acid accumulation, and identifying gene targets to develop effective therapeutic treatments.
Sterol Regulatory Element Binding Protein 1c (SREBP-1c) is a transcription factor of the basic helix-loop-helix leucine zipper (bHLH-Zip) family that controls the expression of genes of the triglyceride and cholesterol synthesis pathways. SREBP-1c has emerged as the central mediator of insulin action on carbohydrate and lipid metabolism in the liver, and its activity is increased in animal models of obesity and type 2 diabetes. Its role in the pathogenesis of diabetes is being evaluated in animal models.
In recent years it has become clear that microRNA are crucial modulators of biological processes, affecting responses as important as the developmental stage or the cell cycle. Dr. Morral’s lab has identified have identified microRNA that are dysregulated in the liver of type 2 diabetes animal models. Studies addressing the contribution of these microRNA in the development of type 2 diabetes are ongoing.
To address these questions, Dr. Morral is using gene transfer approaches with helper-dependent adenovirus vectors. Adenoviral vectors are very efficient at transducing hepatocytes and the helper-dependent vector system resulted in minimal toxicity and long-term persistence of transgenes in mice and non-human primates. Dr. Morral’s lab is pioneer in the use of this type of vector to express short hairpin RNA (shRNA) in the liver. In recent years, RNAi has become the cornerstone of gene function studies, circumventing the limitations of knock-out animals and shortening the otherwise long process of target identification and validation.
Ahn, M., Witting, S.R., Ruiz, R., Saxena, R., Morral, N. Constitutive expression of shRNA in vivo triggers build up of mature hairpin molecules. Human Gene Therapy. In press.
Ruiz, R., Witting, S.R., Saxena, R., Morral, N. Robust hepatic gene silencing for functional studies using helper-dependent adenovirus vectors. Human Gene Therapy 20:87-94 (2009).
Witting, SR., Brown, M., Saxena, R., Nabinger, S., Morral, N. Helper-dependent adenovirus-mediated shRNA expression in the liver activates the interferon response. Journal of Biological Chemistry 283:2120-2128 (2008).
Morral, N., Edenberg, HJ., Witting, SR., Altomonte, J., Chu, T., Brown, M. Effects of glucose metabolism on regulation of genes of fatty acid synthesis and triglyceride secretion in the liver. Journal of Lipid Research 48:1499-1510 (2007).
Morral, N. Novel targets and therapeutic strategies for type 2 diabetes. Trends Endocrinol. Metab. 14:169-175 (2003).
Morral, N., McEvoy, R., Dong, H., Meseck, M., Altomonte, J., Thung, S.N., Woo, S.L.C. Adenovirus-mediated overexpression of glucokinase in the liver as an adjuvant treatment for type 1 diabetes. Human Gene Therapy 13:1561-1570 (2002).
Morral, N., O’Neal, W.K., Rice, R., Leland, M., Kaplan, J., Piedra, P.A., Zhou, H., Parks, R., Velji, R., Aguilar-Cordova, E., Wadsworth, S., Graham, F.L., Kochanek, S., Carey, K.D., Beaudet, A.L. Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proceedings of the National Academy of Sciences USA (Track II) 96:12816-12821 (1999).