A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes
NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases
About This Grant
.PROJECT SUMMARY—NEWGARD/ZHANG ./ Over the past 20 years, our laboratory has used tools available in the Duke Molecular Physiology Institute (DMPI) metabolomics core laboratory to identify strong associations between branched-chain amino acids (BCAA) and a cluster of related metabolites with chronic cardiometabolic diseases. In part through our studies, it is now well- established that BCAA and related metabolites are predictive of incident diabetes and intervention outcomes and highly responsive to therapeutic interventions. Our mechanistic studies in animal models have established causal connections between BCAA and disease-related phenotypes such as insulin resistance, hepatic steatosis, and cardiac protein synthesis. The current proposal is based on a set of recent discoveries in this realm that provide novelty, innovation, and translational relevance for our work: 1) We found that largely unrecognized intermediates in the BCAA catabolic pathway, the branched-chain hydroxyacids (BCHA), are generated from branched-chain ketoacids (BCKA) in skeletal muscle via the action of an NADH-requiring dehydrogenase activity, and then shuttled to the liver where they are reconverted to BCKA to engage with branched-chain ketoacid dehydrogenase (BCKDH). 2) Using a stable isotope labeled BCHA, [U-13C] 2-OHIV, we determined that BCHA catabolism to distal mitochondrial metabolites is higher in livers of female compared to male rats; 3) We have identified two enzymes in liver capable of catalyzing the BCHA to BCKA reaction that are distinct from the enzyme that catalyzes BCKA to BCHA in muscle, with one of these having dramatically different activities in male compared to female livers, possibly explaining the enhanced propensity for BCHA catabolism in females; 4) The rate of BCHA catabolism in female rats links to increases in hepatic threonine (Thr) levels and lowering of liver fat relative to male rats. We propose that BCHA catabolism, Thr, and liver fat are linked by the Thr catabolic product 2-ketobutryate (2-KB), an alternate BCDKH substrate, and by an anti- steatotic effect of Thr. On this backdrop of new findings, we propose the following specific aims: 1) To investigate the impact of sex, genetics, and nutritional status on regulation of lipid and BCAA metabolism in the liver; 2) To investigate the mechanism(s) underlying preferential hepatic catabolism of BCHA in female animals; 3) To investigate sex-dependent regulatory links between Thr, BCHA metabolism, and liver fat. This work will define mechanisms connecting sex-dependent differences in BCAA catabolism with metabolic disease risk, thereby contributing to development of new therapeutic strategies to benefit both sexes.
Grant Summary
A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes is a NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases grant providing up to $821K for university, nonprofit, healthcare org. Applications are due 2030-03-31 (open). Check eligibility and apply with FindGrants.
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Up to $821K
2030-03-31
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A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes: Frequently Asked Questions
Who is eligible for the A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes?
A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes is offered by NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes provide?
A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes provides up to $821K per award from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes deadline?
Applications for A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes are due 2030-03-31 (open). Because deadlines can change, verify the date with the funder, NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes?
To apply for A novel circuit in BCAA catabolism that affects cardiometabolic disease phenotypes, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases.