Mitochondria play a critical role in the energy homeostasis of the cell and the intact animal. Mitochondria oxidize substrates such as lipids and glucose, thereby serving as a central control point for fuels which are dysregulated in human type 2 diabetes. Recent data suggests that human type-2 diabetes is associated with lower expression of the mitochondrial OXPHOS system and their regulators, the PGC-1 coactivators, in muscle. Our recent unpublished genetic data clearly indicate that reduced PGC-1a levels in muscle can cause abnormal glucose tolerance, even in the heterozygous KO state. We propose here an integrated approach to develop chemical compounds that can modulate the PGC-1 coactivators and/or mitochondrial function in both cells and animals. The goal is to establish proof of concept that chemical manipulations of these systems can have a benefit in obesity and type-2 diabetes. We will utilize chemical libraries that include a large number of FDA-approved drugs and drug-like compounds, as well as novel chemical libraries produced at the Broad Institute. We will also investigate molecular targets of novel compounds where the target is not known, using a novel method involving the use of recombinant yeast strains.
Specific Aim 1 will utilize mitochondrial-based screens to find compounds that can control mitochondria number, membrane potential and ATP synthesis.
Specific Aim 2 will perform screens that will identify compounds that modulate the expression of PGC-1a and PGC-1beta, and their function in mitochondrial biology.
Specific Aim 3 will utilize a novel method using recombinant yeast strain to identify targets that are being altered by novel chemical matter arising from Aims 1 and 2. In all cases, we will use cell-based screens of mitochondrial function and insulin-resistance. In addition, we will test the compounds arising from these screens in well-established animal models of obesity, insulin resistance and type-2 diabetes. All of these projects will make use of chemical screening at the Broad Institute and the animal resources at the DFCI. Together, this highly integrated and collaborative project has a high likelihood of providing proof of concept for a novel avenue to the therapeutics of obesity and diabetes.
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| 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 |
| 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 |
| 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 |
| 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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