We are in the midst of a worldwide epidemic in type 2 diabetes (T2D) that is exacerbated by an increasingly conservative pharmaceutical industry that is now desperate for new targets. A growing body of evidence implicates altered mitochondrial function in the pathogenesis of T2D and obesity. For example, mitochondrial metabolism is critical in the control of glucose stimulated insulin secretion, hepatic gluconeogenesis, and peripheral fuel oxidation. The only known direct target of metformin, one of the most useful agents for treating T2D, is a mitochondrial complex. Reduced mitochondrial mass/function have been documented in the skeletal muscle of humans with obesity and T2D, and during aging, and reversible with exercise. Brown fat, which expends chemical energy through mitochondrial uncoupling, has recently emerged as a possible therapeutic target for human obesity. Collectively, these observations raise the exciting hypothesis that modulating mitochondrial physiology may help prevent or reverse the pathophysiology of T2D and obesity. The goal of this R24 project is to discover a mechanistically diverse collection of small molecules with desirable pharmacologic properties that can modulate mitochondrial energetics in vivo by targeting transcriptional programs, translational programs, and direct mitochondrial physiology. Our highly integrated project brings together experts in mitochondrial biogenesis, bioenergetics, chemical screening, and medicinal chemistry, to build and pursue this bold therapeutic hypothesis.
In Aim 1 we will follow-up on exciting preliminary data that has revealed a novel small molecule and its target, a plasma membrane ion channel that controls mitochondrial biogenesis via a transcriptional mechanism. Using this validated screening strategy, we will screen for additional novel small molecules acting via transcriptional mechanisms that promote brown fat differentiation.
In Aim 2 we will follow-up on a large-scale chemical screen that is designed to discover small molecules that work at the level of post-translational modifications to influence mitochondrial biogenesis.
In Aim 3 we will capitalize on the recent discovery of mitochondrial calcium channel subunits, enabled by the previous funding period of this grant, and screen for novel drugs that directly target mitochondrial physiology and energetics through targeting mitochondrial calcium flux. For all three aims we will collaborate closely with leading chemists at Broad Institute and Scripps to perform in-depth lead optimization and formulation and evaluate the novel drugs both in cultured cells as well as in rodent models. If successful, this collaborative project could result in the discovery of mechanistically diverse small molecules that will advance our fundamental understanding of the contribution of mitochondrial metabolism to the development of T2D, while also helping to launch a potentially brand new class of therapeutics for this growing epidemic.
We are experiencing a worldwide epidemic of type II diabetes and obesity, and it is imperative that biomedical scientists find new drug targets that can improve these conditions. This group of investigators is using chemical biology methods to identify tractable drug targets that can improve metabolic diseases through actions on mitochondrial biology and cellular energetics.
| Hatting, Maximilian; Tavares, Clint D J; Sharabi, Kfir et al. (2018) Insulin regulation of gluconeogenesis. Ann N Y Acad Sci 1411:21-35 |
| Shen, Hongying; Campanello, Gregory C; Flicker, Daniel et al. (2017) The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12. Cell 171:771-782.e11 |
| Kamer, Kimberli J; Grabarek, Zenon; Mootha, Vamsi K (2017) High-affinity cooperative Ca2+ binding by MICU1-MICU2 serves as an on-off switch for the uniporter. EMBO Rep 18:1397-1411 |
| Sharabi, Kfir; Lin, Hua; Tavares, Clint D J et al. (2017) Selective Chemical Inhibition of PGC-1? Gluconeogenic Activity Ameliorates Type 2 Diabetes. Cell 169:148-160.e15 |
| Tavares, Clint D J; Sharabi, Kfir; Dominy, John E et al. (2016) The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1? Transcriptional Coactivator. J Biol Chem 291:10635-45 |
| Rines, Amy K; Sharabi, Kfir; Tavares, Clint D J et al. (2016) Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov 15:786-804 |
| Stechschulte, L A; Czernik, P J; Rotter, Z C et al. (2016) PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption. EBioMedicine 10:174-84 |
| Barrow, Joeva J; Balsa, Eduardo; Verdeguer, Francisco et al. (2016) Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations. Mol Cell 64:163-175 |
| Sharabi, Kfir; Tavares, Clint D J; Rines, Amy K et al. (2015) Molecular pathophysiology of hepatic glucose production. Mol Aspects Med 46:21-33 |
| Marciano, David P; Kuruvilla, Dana S; Boregowda, Siddaraju V et al. (2015) Pharmacological repression of PPAR? promotes osteogenesis. Nat Commun 6:7443 |
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