Document text
Principal Investigator: Arianne Caudal
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $74,284
Funding agency: National Heart Lung and Blood Institute
Project Summary
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.
Terms: <2-dimensional><3-D><3-Dimensional><3D><Ablation><Acceleration><Adult-Onset Diabetes Mellitus><Affect><Age><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autopsy><Binding><Binding Proteins><Biological><Biomedical Research><Blood Vessels><Body Tissues><Calcium><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular><Cardiovascular Agents><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Drugs><Cardiovascular Models><Cardiovascular Organ System><Cardiovascular system><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Signaling><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Clinical Trials><Co-Transporters><Communities><Complex><Conditioned Culture Media><Conditioned Medium><Coupled><D-Glucose><Death><Development><Dextrose><Disease><Disorder><Drugs><Dysfunction><Endothelial Cells><Excretory function><Fibroblasts><Functional disorder><Genetic><Glucose><Heart><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><Hospital Admission><Hospitalization><Human><Hypertension><Individual><Intracellular Communication and Signaling><Investigators><Isotopes><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Urinary System><Knock-out><Knockout><LC/MS><Ligand Binding Protein><Ligand Binding Protein Gene><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Maturity-Onset Diabetes Mellitus><Measurement><Measures><Medication><Metabolic><Metabolic Diseases><Metabolic Disorder><Mitochondria><Modeling><Modern Man><Molecular><Molecular Interaction><Myocardial><NIDDM><Na element><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Oxygen Consumption><Pathogenesis><Pathologic><Pathology><Pathway interactions><Patients><Peptides><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phenotype><Physiopathology><Population><Preclinical Testing><Proliferating><Protective Agents><Protective Drugs><Protein Binding><Protein Cleavage><Proteins><Proteolysis><Proteomics><Protocol><Protocols documentation><Public Health><Research><Research Personnel><Researchers><Resolution><Respiration><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Sodium><Stable Diabetes Mellitus><Strains Cell Lines><Subcellular Process><System><Systems Biology><T2 DM><T2D><T2DM><Therapeutic><Thesaurismosis><Tissues><Training><Type 2 Diabetes Mellitus><Type 2 diabetes><Type 2 diabetic><Type II Diabetes Mellitus><Type II diabetes><Type II diabetic><Validation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Ventricle Remodeling><Ventricular Cardiac Remodeling><Ventricular Myocardial Remodeling><Ventricular Remodeling><absorption><adult onset diabetes><ages><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><biobank><biologic><biological signal transduction><biorepository><bound protein><cardiac failure><cardiac tissue engineering><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><cell type><circulatory system><cultured cell line><design><designing><developmental><diabetic><diabetic cardiomyopathy><diabetic cardiopathy><diabetic cardiopathy disease><diabetic cardiopathy disorder><diabetic cardiovascular disease><diabetic cardiovascular disorder><diabetic patient><directed differentiation><disease phenotype><drug/agent><endothelial progenitor><endothelial progenitor cell><endothelial stem cell><engineered heart tissue><ethnic diversity><ethnically diverse><excretion><fascinate><glucose uptake><glycemic control><hiPSC><high blood pressure><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><iPS><iPSC><iPSC technology><iPSCs><in vitro Model><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell technology><inducible pluripotent stem cell><inhibitor><innovate><innovation><innovative><insight><ketosis resistant diabetes><knock-down><knockdown><liquid chromatography mass spectrometry><maturity onset diabetes><metabolic phenotype><metabolism disorder><metabolism measurement><metabolomics><metabonomics><metabotype><migration><mitochondrial><monolayer><mortality><myocardial remodeling><necropsy><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><pathway><patient retention><pharmaceutical><postmortem><pre-clinical testing><prevent><preventing><progenitor cell model><progenitor model><protective effect><renal><resolutions><respiratory mechanism><sex><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><symporter><three dimensional><tissue culture><tool><two-dimensional><type 2 DM><type II DM><type two diabetes><validations><vascular>