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Principal Investigator: Chengyi Tu
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $151,637
Funding agency: National Heart Lung and Blood Institute
Tachycardia, or abnormally fast heart rate, is an important risk factor for cardiovascular morbidity and mortality.
Prolonged tachycardia is known to induce cardiomyopathy in patients who have no prior structural heart diseases.
Moreover, transient tachycardia, frequently observed in heart failure patients, can exacerbate the cardiovascular
outcome. However, very little is known about the molecular drivers underlying tachycardia-induced cardiac
dysfunction. This gap in our knowledge hinders the development of more effective heart failure treatment,
especially for patients with hard-to-control tachycardia. This K99/R00 proposal will leverage recent advances in
induced pluripotent stem cell (iPSC), tissue engineering, and multiomics technologies to uncover the molecular
signaling pathways critically involved in the pathology of tachycardia-related heart disease. The applicant, Dr.
Chengyi Tu, has established and validated an in vitro tachycardia platform using engineered heart tissue (EHT).
In Aim 1, Dr. Tu will perform metabolomic and transcriptomic profiling of EHTs with or without tachypacing. To
validate the physiological relevance of the EHT model, canine samples from tachypacing-induced heart failure
will also be profiled. Preliminary data from the EHTs and the canine samples coherently indicate that the
disruption of glycolysis homeostasis may underly the impairment of cardiac function by tachycardia.
Metabolomics analysis shows that tachypacing in EHTs resulted in a selective accumulation of glycolysis
intermediates such as glyceraldehyde 3-phosphate (GA3P) and 3-phosphoglycerate (3PG). Interestingly,
promotion of fatty acid metabolism accelerated the recovery of cardiac contractility in tachypaced EHTs. Based
on these novel results, Aim 2 will focus on elucidating how different glycolysis intermediate metabolites affect
the function of cardiomyocytes, which has yet to be systematically examined. Lastly, Aim 3 (R00 phase) will
employ state-of-the-art mass spectrometry workflow to screen for novel binding targets of glycolysis
intermediates in cardiac cells, and examine the potential therapeutic benefits of manipulating these targets. This
K99/R00 proposal will be guided by an excellent mentoring team with diverse expertise, including mentor Dr.
Joseph Wu (iPSCs and cardiac biology), co-mentor Dr. Sanjiv Narayan (arrhythmia), advisors Dr. Michael
Snyder (genetics and multi-omics), Dr. Yuqin Dai (metabolomics), Dr. Stanley Qi (CRISPR interference) and Dr.
Beth Pruitt (bioengineering), as well as collaborators Dr. Fabio Recchia (canine model) and Dr. Donald Bers
(cardiac physiology). To sum up, the completion of the proposed study will significantly advance our mechanistic
understanding of how tachycardia adversely affects the heart, thereby creating new opportunities for therapeutic
interventions. The proposed training will significantly strengthen and expand Dr. Tu’s research expertise,
providing substantial momentum to his transition toward an independent cardiovascular researcher.
Terms: <3-D><3-Dimensional><3-Phosphoglyceraldehyde><3-phosphoglycerate><3D><ATP-3-phospho-D-glycerate 1-phosphotransferase><Abnormal heart structure><Acceleration><Address><Adrenergic beta-Antagonists><Adrenergic beta-Blockers><Advisory Committees><Affect><Animals><Arrhythmia><Autoregulation><Binding><Biology><Biomedical Engineering><Biopsy><CRISPR interference><CRISPR-dCas9-mediated repression><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><Calcium><Canine Species><Canis familiaris><Cardiac><Cardiac Arrhythmia><Cardiac Chronotropism><Cardiac Diseases><Cardiac Disorders><Cardiac Electrophysiologic Techniques><Cardiac Electrophysiological Diagnostics><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Ch'i><Chemicals><Clustered Regularly Interspaced Short Palindromic Repeats interference><Coupled><Critical Paths><Critical Pathways><Custom><D-Glucose><Data><Data Engineering><Development><Dextrose><Dogs><Dogs Mammals><Dysfunction><Enzyme Gene><Enzymes><Event><Fatty Acid Metabolism Pathway><Functional disorder><Future><G-Proteins><GAPD><GTP-Binding Proteins><GTP-Regulatory Proteins><Gene Inactivation><Gene Silencing><Genes><Genetic><Glucose><Glyceraldehyde 3-Phosphate><Glyceraldehyde-3-Phosphate Dehydrogenases><Glyceraldehydephosphate Dehydrogenase><Glycolysis><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Heart><Heart Arrhythmias><Heart Diseases><Heart Muscle Cells><Heart Rate><Heart Vascular><Heart failure><Heart myocyte><History><Homeostasis><Human Engineering><Impairment><In Vitro><Investigators><Knowledge><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mentors><Metabolic><Metabolic Diseases><Metabolic Disorder><Modeling><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Myocardial Diseases><Myocardial Disorder><Myocardial depression><Myocardial dysfunction><Myocardiopathies><Myoglobin><Outcome><Oxidative Stress><Pathology><Pathway interactions><Patients><Phase><Phenotype><Phosphoglyceraldehyde Dehydrogenase><Phosphoglycerate Kinase><Physiologic><Physiological><Physiological Homeostasis><Physiology><Physiopathology><Play><Prognosis><Protein Cleavage><Protein Subunits><Proteins><Proteolysis><Qi><RNA Seq><RNA sequencing><RNAseq><Recording of previous events><Recovery><Regulation><Research><Research Personnel><Researchers><Risk Factors><Role><Sampling><Signal Pathway><Sum><System><Tachyarrhythmias><Tachycardia><Task Forces><Technology><Therapeutic><Therapeutic Intervention><Thesaurismosis><Tissue Engineering><Tissue Model><Training><Treatment Failure><Triosephosphate Dehydrogenase><Validation><Ventricular Dysfunction><advisory team><analysis pipeline><beta blocker><beta-Adrenergic Blocking Agents><beta-Adrenergic Receptor Blockaders><bio-engineered><bio-engineers><bioengineered tissue><bioengineering><biological engineering><canine><canine animal model><canine model><cardiac dysfunction><cardiac electrophysiology><cardiac failure><cardiac function><cardiac tissue engineering><cardiomyocyte><cardiovascular risk><cardiovascular risk factor><circulatory system><customs><design><designing><developmental><dog model><domestic dog><engineered heart tissue><engineered tissue><experience><fatty acid metabolism><feasibility testing><function of the heart><global gene expression><global transcription profile><glyceraldehyde phosphate><glycerate 3-phosphate><heart disorder><heart dysfunction><heart electrophysiology><heart function><histories><human data><iPS><iPSC><iPSCs><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><intervention therapy><metabolic profile><metabolism disorder><metabolism measurement><metabolomics><metabonomics><mortality><multiomics><multiple omics><myocardium disease><myocardium disorder><novel><panomics><pathophysiology><pathway><progenitor biology><progenitor cell biology><repressing CRISPR-dCas9 system><skills><small molecular inhibitor><small molecule inhibitor><social role><stem and progenitor biology><stem cell biology><structural cardiac abnormality><structural cardiac anomaly><structural cardiac defect><structural heart condition><structural heart defect><structural heart disease><tachyrhythmia><therapy failure><three dimensional><transcriptional silencing><transcriptome><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><transcriptomics><validations>