DEGREE (if applicable)

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1 OMB No and (Rev. 10/15 Approved Through 10/31/2018) NAME: Tong, Carl Wei-Chan BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. era COMMONS USER NAME (credential, e.g., agency login): POSITION TITLE: Assistant Professor (tenure-track) EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Texas A&M University, College Station, TX BS 05/1985 Electrical Engineering Air Force Institute of Technology, Dayton, Ohio MS 12/1986 Electrical Engineering Texas A&M University Health Science Center College of Medicine, College Station, TX MD/PhD 05/2002 Duke University Medical Center, Durham, NC 06/2005 American Board of Internal Medicine Certification 08/2005 Medicine (MD)/Medical Physiology (PhD) Internal Medicine Residency Internal Medicine Board Certification University of Wisconsin, Madison, WI 06/2010 Cardiology Fellowship American Board of Internal Medicine Certification 10/2010 American Board of Internal Medicine Certification 11/2014 Cardiovascular Disease Board Certification Advanced Heart Failure and Transplant Cardiology Board Certification A. Personal Statement I have been caring for heart failure patients since Their suffering has moved me to complete a very long process of becoming a cardiologist and initiating research in heart failure. I strive to attain the long-term goals of elucidating mechanisms that cause heart failure, translate the new understanding toward treatment, and directly helping patients as a physician. I have established genetically modified mouse models of systolic dysfunction, diastolic dysfunction, and enhanced diastolic function. I also have established surgical mouse models of systolic and diastolic dysfunction. Furthermore, my laboratory has developed full range of functional testing from whole-mouse physiology to single isolated cardiac myocytes. Methods include voluntary running wheel, echocardiography, intra-cardiac pressure-volume measurements, simultaneous force/intracellular calcium measurements on intact papillary muscles, phosphorylation studies, isolation of living immune cells from whole heart with follow-on flow cytometry analysis, quantitative RT-PCR to detect gene expression differences, and host of other biochemistry techniques. A particular focus of my research is elucidating mechanisms that can treat heart failure with preserved ejection fraction (HFpEF). Due to unforeseen events, I had to be the medical directory for heart transplant & mechanical circulatory support program for nearly 2 years. I performed inpatient and outpatient care, re-organized teams, wrote all transplant related protocols, standardized patient follow-up, helped with recruiting physicians, and led team through Joint Commission evaluation. With the program stabilizing, I voluntarily resigned the position in June 2015 to focus on research. As reported by the publicly accessible, Scientific Registry of Transplant Recipients (SRTR), the one-year survival of our heart transplant recipients improved from 80% to 100% during my tenure. Afterwards, I continue to care for heart failure patients.

2 Currently, we are actively pursuing phosphorylation of cardiac myosin binding protein C (cmybp-c) as a potential treatment for diastolic dysfunction by developing new knock-in mouse models and establishing capability to make engineered heart tissue (EHT) from human induced pluripotent stem derived cardiac myocytes. My institution has recently provided additional laboratory space and specialized equipment (automated test system for 24-well plat format EHT cultures) to support this new pursuit. Separately, I recognize that vascular system plays an important in development of heart failure. For example, reduced microvascular density correlated with HFpEF. Our diastolic dysfunction mouse model exhibited reduced visible coronary vascular density after trans-aortic constriction challenge while WT increased density. We are also able to make simultaneous measurements of vessel inner diameter and intracellular calcium to understand underlying mechanisms. In the future, we will work to identify the link between myofilament protein and vascular function. Furthermore, we will also aim to incorporate vascular development in the EHTs. B. Positions and Honors Positions : 2nd Lieutenant, graduate student, United States Air Force, Air Force Institute of Technology : Lieutenant-Captain, United States Air Force, Space Systems Division : Graduate Teaching Assistant, Biomedical Engineering Department, Texas A&M University : MD/PhD student, Texas A&M University Health Science Center College of Medicine : Intern-Resident, Internal Medicine, Duke University Medical Center : Fellow, Internal Medicine/Cardiovascular Medicine Program, University of Wisconsin : Interim Medical Director of Heart Transplant and mechanical circulatory support program, Department of Internal Medicine/Cardiology Division, Baylor Scott & White Health Central Texas 2010-present: Cardiologist (Advanced Heart Failure/Left Ventricular Assist Device/Heart Transplant Cardiologist), Baylor Scott & White Health Central Texas 2010-present: Assistant Professor tenure track, Dept of Medical Physiology, Texas A&M University HSC College of Medicine Honors Eta Kappa Nu (Electrical Engineering Honor Society, 1984) Tau Beta Pi (Engineering Honor Society, 1984) United States Air Force Achievement Medal (1991) United States Air Force Commendation Medal (1992) United States Air Force Commendation Medal First Oak Leaf Cluster(1992) Phi Kappa Phi (All Academic Fields Honor Society, 1994) Alvin P. Smith Award for outstanding student in Medical Physiology (Texas A&M University HSC College of Medicine, 1995) Alpha Omega Alpha (Medical Honor Society, 1997) First Place oral abstract, Texas A&M University Student Research Week 2000, Graduate Level Biological Sciences II, Oral Category, College Station, TX First Place oral abstract, Texas A&M University Health Science Center 2001 Graduate Research Symposium, College Station, TX Outstanding Abstract Award, Thick and Thin Filament Regulation in Striated Muscle Meeting, May 4-6, 2008 Madison, Wisconsin Selected as one of the Top 3 abstracts for November 18th,2009 American Heart Association Scientific Sessions, Orlando FL C. Contribution to Science 1. Cardiac Myosin Binding Protein-C Modulates Diastolic Function of the Heart HFpEF is occurrence of heart failure (HF) despite left ventricular ejection fraction 50%. Prevalence of HFpEF has increased to ~50% of all HF diagnoses. HFpEF does not have any effective treatment. Diastolic dysfunction is the main contributor to HFpEF. Cardiac myosin binding protein-c (cmybp-c) is a 140 KD regulatory protein on the thick filament of the heart that regulates cross-bridge cycling. I hypothesized that cmybp-c mediates diastolic function.

3 (1) cmybp-c phosphorylation increases the rate of cross-bridge cycling to increase both contractility and lusitropy. (2) Loss of cmybp-c phosphorylation leads to mouse phenotype resembling HFpEF in humans (i.e., LVEF > 50%, diastolic dysfunction, and heart failure). (3) Phosphorylation of cmybp-c enhances diastolic function by increasing cross-bridge detachment rate > attachment rate 2. We also found cmybp-c phosphorylation affected vascular density. We are in process of quantifying and elucidating its effects. Impact on Science and Healthcare: Demonstrated that modulation of cross-bridge detachment rate is a critical mediator of diastolic function. This mechanism can provide for future treatment of HFpEF. Developed hypothesis. Helped to make transgenic on cmybp-c (-/-) background mouse models of phosphorylation-deficient and phosphorylation-mimetic of cmybp-c. Tested hypothesis using voluntary running wheel, echocardiography, intra-cardiac pressure-volume measurements, simultaneous force and intracellular calcium concentration [Ca 2+ ] i measurements on intact papillary muscle, and a host of biochemistry studies. Personally, integrated simultaneous force/[ca 2+ ] i equipment suites (Madison WI and Temple TX), developed protocols, and taught intact papillary muscle force/[ca 2+ ] i technique to multiple researchers. a) Tong CW, Stelzer JE, Greaser ML, Powers PA, Moss RL. Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ Res Oct 24;103(9): doi: /CIRCRESHAHA PMID: ; PMCID: PMC b) Colson BA, Patel JR, Chen PP, Bekyarova T, Abdalla MI, Tong CW, Fitzsimons DP, Irving TC, Moss RL. Myosin binding protein-c phosphorylation is the principle mediator of protein kinase A effects on thick filament structure in myocardium. J Mol Cell Cardiol Nov;53(5): doi: /j.yjmcc PMID: ; PMCID: PMC c) Rosas PC, Liu Y, Abdalla MI, Thomas CM, Dusio GF, Kidwell D, Mukhopadhyay D, Kumar R, Mitchell BM, Baker KM, Fitzsimons DP, Powers PA, Patel BG, Warren CM, Solaro RJ, Moss RL, Tong CW. Phosphorylation of cardiac myosin binding protein-c is a critical mediator of diastolic function. Circ Heart Fail May;8(3): doi: /CIRCHEARTFAILURE PMID: ; PMCID: PMC d) Tong CW, Wu X, Liu Y, Rosas PC, Saddayappan S, Hudmon A, Muthuchamy M, Powers PA, Valdivia HH, Moss RL. Phosphoregulation of cardiac inotropy via myosin binding protein-c during increased pacing frequency or β1-adrenergic stimulation. Circ Heart Fail May;8(3): doi: /CIRCHEARTFAILURE PMID: ; PMCID: PMC Cardiac Myosin Binding Protein-C modulates immune response to protect heart function Immune response during sepsis and heart transplant rejection causes cardiac dysfunction. Presence of diastolic dysfunction but not necessary systolic dysfunction increased mortality in sepsis. (1) Circulating cmybp-c increased with exercise stress and major cardiovascular event risk, but did not correlate with cardiac damage. This pattern suggested a cardiac protective role for circulating cmybp-c. (2) In mouse models, presence of cmybp-c recruited protective immune cells to the heart during sepsis like inflammatory state. Impact on Science and Healthcare: Results can lead to new methods to prevent and treat heart failure Developed hypothesis. Designed, directed, and funded preliminary studies. Currently in writing phase 4. Strongly-Bound cross-bridges recruiting others cross-bridge provide majority of force generation during contraction Small amount of increases in [Ca 2+ ] i cannot explain the positive force/frequency relationship of the cardiac muscle.

4 (1) Peak force occurs well after peak [Ca 2+ ] i (2) Strongly-bound cross-bridges recruiting other cross-bridges during initial [Ca 2+ ] i decay produces a hysteresis force/[ca 2+ ] i relationship to generate majority of the force (rising [Ca 2+ ] i initially cause small force increases but force continues to increase during [Ca 2+ ] i decay so the peak force occurs at much lower [Ca 2+ ] i, i.e., force follows a low amplitude convex path with rising [Ca 2+ ] i but high amplitude concave path with decreasing [Ca 2+ ] i ) (3) The magnitude of the hysteresis increases with increasing pacing frequency due to predominantly crossbridge contribution but much smaller extent to rising [Ca 2+ ] i (4) Phosphorylation of cmybp-c and cardiac troponin-i (ctni) both alter the shape of force/[ca 2+ ] i hysteresis to modulate heart muscle function Impact on Science and Health: The results show cross-bridge attachment and subsequent recruitment of other cross-bridges provide the predominant force generation during a cardiac contraction. This provides the rationale for using direct crossbridge activation to treat systolic dysfunction heart failure. Developed hypothesis. Worked with a team of physicists to build novel surface plasmon resonance apparatus that specifically measures cross-bridge attachment/detachment within intact sarcomeres. Integrated different equipment and build necessary additions to complete a suite of equipment to simultaneous measure force/[ca 2+ ] i on intact papillary muscles (College Station TX). Developed protocols for both suites of equipment. Tested hypothesis on wild-type mice. a) Tong CW, Kolomenskii AA, Schuessler HA, Trache A, Granger HJ, Muthuchamy M; Measurements of the Crossbridge Attachment/Detachment Process within Intact Sarcomeres Using the Surface Plasmon Resonance. Biochemistry Nov 20;40(46): PMID: b) Tong CW, Gaffin RD, Zawieja DC, Muthuchamy M; Roles of phosphorylation of myosin binding protein-c and troponin I in mouse cardiac twitch dynamics. J Physiol Aug 1;558(Pt 3): doi: /jphysio PMID: ; PMCID: PMC Development of Engineered Heart Tissue Mouse models cannot address multiple combinatorial possibilities of cardiac myosin binding protein-c phosphorylation. Three-dimensional engineered heart tissue (EHT) allows one to express different combination of cmybp-c phosphorylation patterns for testing. Furthermore, one needed to develop methods that can be used to make EHTs from human induced pluripotent stem-cells (HiPSC). (1) Is able to EHT from cmybp-c (-/-) neonatal mouse hearts to allow expression of different types of cmybp-c (2) Electrical pacing EHTs can improve its function (3) EHTs can be maintained over 2-weeks without losing its function or cardiac phenotype Impact on Science and Health: Provide future testing platform using HiPSC derived engineered heart tissue for disease mechanism identification and treatment. Personal Role Promoted the idea of making EHT from cmybp-c (-/-) neonatal cardiac myocytes. Designed and optimized an electrical pacing protocol to enhance EHT development and function. Integrated an entire testing suite that simultaneously measures force/[ca 2+ ] i on EHTs. Taught researchers on the techniques so they can carry the work forward. Cardiology fellowship only allowed 2-years of research. I spent significant amount of 2-year research time on cmybp-c mouse models, thereby shortchanged further EHT work. I had to leave research and return to clinical portion of cardiology fellowship; therefore, others finished the EHT work that I started. a) De Lange WJ., Hegge BS, Tong CW, Brost TM, Moss RL, Ralphe JC; Neonatal mouse-derived engineered cardiac tissue: a novel model system for studying genetic heart disease. Circ Res Jun 24;109(1):8-19. doi: /CIRCRESAHA PMID: ; PMCID: PMC b) Stoehr A, Neuber C, Baldau C, Vollert I, Fredrich, FW, Flenner F, Carrier L, Eder A, Schaaf S, Hirt MN, Aksehirlioglu B, Tong CW, Moretti A, Eschenhagen T, Hansen A; Automated analysis of contractile force and Ca2+ transients in engineered heart tissue. Am J Physiol Heart Circ Physiol May;306(9):H doi: /ajpheart PMID: ; PMCID: PMC

5 6. Resist Aging Related Development of Diastolic Dysfunction The aging heart demonstrates deterioration of diastolic function. Normally phosphorylatable cmybp-c hearts showed deterioration of diastolic function at 12-months in mice. However, cmybp-c phosphorylation mimetic hearts retained enhanced diastolic function at >18 months of age. Personal Role Developed the hypothesis. Aged the existing mouse lines to test the hypothesis. I m currently conducting an 18-months aging project, due to be finished at the end of a) Rosas PC, Liu Y, Abdalla MI, Thomas CM, Dusio GF, Kidwell D, Mukhopadhyay D, Kumar R, Mitchell BM, Baker KM, Fitzsimons DP, Powers PA, Patel BG, Warren CM, Solaro RJ, Moss RL, Tong CW. Phosphorylation of cardiac myosin binding protein-c is a critical mediator of diastolic function. Circ Heart Fail May;8(3): doi: /CIRCHEARTFAILURE PMID: ; PMCID: PMC List of Accessible Publications D. Ongoing Research Support Active [Huffines Faculty Research Grant] (PI: Tong) 09/01/ /01/2017 JL Huffines Institute for Sports Medicine and Human Performance Cardiac Myosin Binding Protein-C phosphorylation is essential to preserve diastolic function to support exercise tolerance in aging hearts This effort ages mice to 15 months and then place them with voluntary running wheels. The hypothesis is that cmybp-c phosphorylation can be induced by exercise to reverse diastolic dysfunction. [Temple Campus Research Development] (PI: Tong) 01/01/ /31/2017 Implement an equipment suite that can make and test engineered heart tissue overtime in nondestructive fashion. Completed [K08HL114877] (PI: Tong) 07/01/ /30/2017 National Institutes of Health Contributions of cardiac myosin binding protein-c to healthy and failing hearts The purpose of this grant is to test the hypotheses that cardiac myosin binding protein-c phosphorylation regulates cross-bridge cycling to enhance both contractility (ability to generate force) and lusitropy (ability to relax). A process which contributes to both healthy and failing hearts. [RGP#100439] (PI: Tong) 09/01/ /31/2013 Scott & White Memorial Hospital Roles of cardiac myosin binding protein-c phosphorylation in heart failure The purpose of this proposal was to determine effects of myosin binding protein C phosphorylation on exercise and echocardiographic parameters under in vivo conditions. [11BGIA ] (PI: Tong) 07/01/ /01/2014 American Heart Association Cardiac myosin binding protein-c phosphorylation in heart failure The purpose of this grant was to determine the role myosin binding protein C phosphorylation on diastolic function in mice following cardiac stress (left ventricular overload). [14GRNT ] (Co-PI: Tong, received 50%) 7/1/2014-6/30/2016 American Heart Association Diagnostic and prognostic value of cardiac myosin binding protein-c in ischemia and post-infarction This grant found: all subjects have circulating cmybp-c that increased with exercise stress, basal cmybp-c levels predicted future major cardiovascular events, and basal cmybp-c did not correlate with visible heart damage.