Glycogen is a normal branched polymer of glucose that acts as a reserve of glucose units, to be used for anabolism or as a source of energy. Abnormal glycogen metabolism is associated with some generalized metabolic disorders, most notably type 2 diabetes and insulin resistance, but in addition a number of individual genetic glycogen storage diseases (GSDs) or glycogenoses have been identified. In these, mutations in genes impacting glycogen metabolism result in abnormal glycogen deposits in a variety of tissues, often with serious and even fatal consequences. No truly effective treatments are available for the most serious disorders. Genetic depletion of glycogen levels has recently been shown to have efficacy in alleviating the pathology in a mouse model of Pompe disease. The main premise for this proposal is that suppression of glycogen accumulation is a promising therapeutic approach to combat glycogenoses in general and Pompe disease in particular.
Aim 1 : Identification of small molecule inhibitors of glycogen synthase. We will search for active site and allosteric site inhibitors of glycogen synthase by high-throughput screens using novel assays. Lead compounds will form the basis to develop focused libraries of chemically related molecules to enhance both potency and biological efficacy. Positives from the above screens will be confirmed by more extensive enzyme kinetic study and promising candidates evaluated in model cell systems and then at the whole animal level.
Aim 2 : Medicinal chemistry optimization. Compounds identified in Aim 1 (and Aim 3) will be evaluated for chemical properties and synthetic tractability, refined by purchase and/or the synthesis of focused libraries to develop improved compounds.
Aim 3 : Cell-based analyses of effectors of glycogen accumulation. We have developed novel assays to monitor cellular glycogen accumulation in cells. The assays will be applied to evaluate and validate any candidate glycogen synthase inhibitors identified in Aim 1 as well as an alternative way to screen compound libraries to identify novel inhibitors.
Aim 4 : Testing inhibitors of glycogen accumulation in mouse models of Pompe disease. Compounds identified in Aims 1 - 3 that show most promise will be tested in mice for toxicology and pharmacokinetics. Suitable compounds will then be administered to Pompe mice to assess their effects on glycogen overaccumulation, cardiac hypertrophy and locomotor impairment associated with the disease. In the future, we can test compounds with other mouse models of glycogenoses. Even one new effective drug would be of major importance for Pompe patients and possibly patients with other glycogen storage diseases.

Public Health Relevance

Glycogen is a normal storage form of glucose in tissues but abnormal glycogen stores cause several diseases, including Pompe disease which, in its most severe form, causes death within the first year of life. Experiments with a mouse model of Pompe disease have shown that reducing glycogen alleviates disease symptoms. This proposal seeks to identify small molecule compounds that suppress glycogen accumulation and hence may be developed into drugs to treat Pompe disease and other related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027221-38
Application #
9303330
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Laughlin, Maren R
Project Start
1979-11-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
38
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Irimia, Jose M; Meyer, Catalina M; Segvich, Dyann M et al. (2017) Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem 292:10455-10464
Mahalingan, Krishna K; Baskaran, Sulochanadevi; DePaoli-Roach, Anna A et al. (2017) Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation. Biochemistry 56:179-188
Contreras, Christopher J; Segvich, Dyann M; Mahalingan, Krishna et al. (2016) Incorporation of phosphate into glycogen by glycogen synthase. Arch Biochem Biophys 597:21-9
Scheffler, Tracy L; Park, Sungkwon; Roach, Peter J et al. (2016) Gain of function AMP-activated protein kinase ?3 mutation (AMPK?3R200Q) in pig muscle increases glycogen storage regardless of AMPK activation. Physiol Rep 4:
DePaoli-Roach, Anna A; Contreras, Christopher J; Segvich, Dyann M et al. (2015) Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease. J Biol Chem 290:841-50
Roach, Peter J (2015) Glycogen phosphorylation and Lafora disease. Mol Aspects Med 46:78-84
Irimia, Jose M; Tagliabracci, Vincent S; Meyer, Catalina M et al. (2015) Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice. J Biol Chem 290:22686-98
Garyali, Punitee; Segvich, Dyann M; DePaoli-Roach, Anna A et al. (2014) Protein degradation and quality control in cells from laforin and malin knockout mice. J Biol Chem 289:20606-14
Pederson, Bartholomew A; Turnbull, Julie; Epp, Jonathan R et al. (2013) Inhibiting glycogen synthesis prevents Lafora disease in a mouse model. Ann Neurol 74:297-300
Roach, Peter J; Depaoli-Roach, Anna A; Hurley, Thomas D et al. (2012) Glycogen and its metabolism: some new developments and old themes. Biochem J 441:763-87

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