Understanding metabolic interplay in a human ipsc model of diabetic cardiomyopathy
Ended Project Grant Awarded Last action
- Award ID
- F32HL173968
- Recipient
-
The Leland Stanford Junior University UEI HJD6G4D6TJY5
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $485,708
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date
- Place of performance
- California, USA
Award details come from USAspending.gov.
Description
- Abstract
- Type 2 diabetes (T2D) is a leading cause of death nationwide, with 65% of mortality due to cardiovascular disease. The term "diabetic cardiomyopathy (T2DCM)" refers to a condition with adverse myocardial remodeling in the absence of hypertension and vascular pathology. Although T2D and CVD are tightly intertwined, we lack a deeper understanding of T2DCM at the molecular and cellular levels. Pathological mechanisms within the primary constituents of the heart - cardiomyocytes, fibroblasts, and endothelial cells - are incompletely understood. Furthermore, how these metabolic signals converge within the cardiac microenvironment remains elusive. First developed to treat T2D, sodium-glucose cotransporter-2 inhibitors (SGLT2I) prevent glucose reabsorption by the kidney. However, recent clinical trials of SGLT2I (canagliflozin, dapagliflozin, and empagliflozin) further demonstrated an unexpected and substantial reduction in heart failure hospitalizations in patients with and without T2D. Since SGLT2 is lowly expressed in the heart, its off-target mechanisms present a fascinating opportunity to elucidate cardiac protective targets beyond glycemic control. I hypothesize that metabolic interplay between cardiomyocytes, endothelial cells, and fibroblasts play a role in T2DCM pathogenesis, and SGLT2 inhibition is a tool to dissect cell-specific protective mechanisms. Since access to human cardiac samples is limited by primary culture or post-mortem autopsy, the pre-clinical testing of cardiovascular drugs difficult. Thus, induced pluripotent stem cells (ipscs) have become a valuable platform for biomedical research by providing tissue-specific human cells that retain patients' genetic integrity and display disease phenotypes in a dish. In this F32 proposal, i will harness ipsc technology to generate T2DCM models of cardiovascular cell types for cellular and metabolic phenotyping with and without SGLT2 inhibition (aim 1). The ipscs of T2D patients (10 healthy, 20 T2D) are readily available from the stanford cardiovascular institute biobank. They will be differentiated into three cardiovascular cell types using robust protocols followed by contractility, mitochondrial oxygen consumption rate, cellular (viability, migration, proliferation), and metabolic function (13C-metabolomics) measurements. Next, i will construct ipsc-derived engineered heart tissues for functional phenotyping of cellular interplay (aim 2). I will further determine the SGLT2I-protein interactome using limited proteolysis coupled to liquid chromatography-mass spectrometry (LIP-MS). Using a systems-level approach compatible with complex biological samples will enable elucidation of drug-protein interactions relevant to T2DCM with peptide-level resolution. In summary, this research plan presents a novel, comprehensive view of metabolic mechanisms conferred by T2DCM pathogenesis, and SGLT2 inhibition and can be used as a springboard for discovering new cardiac protective agents. Taken together, this project will bolster an innovative direction for the cardiovascular community while providing me with the necessary training to become an independent researcher of cardiac metabolic disease.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$0 | |
| Amendment | -$52,098 | |
| Amendment | -$52,098 | |
| Amendment | $1,284 | |
| Amendment | $1,284 | |
| Amendment | $76,756 | |
| Amendment | $76,756 | |
| Amendment | $76,756 | |
| Amendment | $4,784 | |
| Amendment | $4,784 | |
| Amendment | $69,500 | |
| Amendment | $0 | |
| Amendment | $69,500 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $69,500 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $69,500 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $69,500 |
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Quick answers
Who received award F32HL173968?
F32HL173968 was awarded to The Leland Stanford Junior University by National Heart Lung and Blood Institute (National Institutes of Health) on September 6, 2024.
How much is award F32HL173968 worth?
$485,708 has been obligated on F32HL173968.
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