| 289 | Chi Keung Lam, Ph.D. | <p>​​Assistant Professor<br></p> | (302) 831-3165 | | lamcg@udel.edu | 221 BPI | 245 BPI | | <ul><li>B.S. - Purdue University</li><li>Ph.D - University of Cincinnati</li><li>Post-doctoral - Stanford University</li><li>Instructor - Stanford University<br></li></ul> | | <p>Heart disease is one of the top killers in the United States and worldwide. With more than 5 millions heart failure cases per year in US, it is alarming that half of those patients cannot survive beyond five years after diagnosis. One major issue is that current therapies are not developed to target the etiology of cardiomyopathy. The long-term goal of my lab is to identify disease mechanisms in various hereditary and acquired cardiac diseases, and develop targeted therapeutic to improve clinical outcome. <br></p><p>Unlike other organs, heart needs to continuously contract and relax rhythmically to ensure proper blood supply to the rest of the body. The center of this regulation is the rise and fall of calcium ions within the cell, as it is essential for the shortening and re-lengthening of myofilaments. Dysregulation of this rhythmic cycle will reduce the efficiency of the pumping action. Furthermore, calcium is also an essential mediator in cell survival/death signaling. Ectopic calcium response can have detrimental outcome in the heart, as it is difficult to reverse damage caused by unwanted cell death due to its limited regenerative capacity. My lab is interested in understanding how calcium is regulated in each compartment in the cardiac cells. By understanding the regulatory machinery in local milieu, we can further explore how calcium dysregulation trigger various stress response. Using both mouse models and human induced pluripotent stem cell (iPSC) platform, we examine the effect of modulating our target protein or gene in cardiac physiology and pathophysiology. The combination of human iPSC and animal studies can complementarily validate mechanisms with human and rodent genetics. The scalable iPSC platform and engineered heart tissue technology also allow us to test compounds or biologics effectively to facilitate drug discovery.<br></p> | <p><strong>1. </strong><strong>Identifying novel regulators for calcium kinetics.</strong> </p><p>Intracellular calcium regulation is essential to maintain normal contractile function of cardiac cells. Calcium dysregulation have been shown to be a hallmark in various types of cardiac diseases. While the importance of calcium in cardiac function has been appreciated for very long time, we still lack the understanding on how calcium is precisely regulated under various physiological conditions. This prevents us from developing proper strategy to correct the fundamental issue. Previously, my works have demonstrated apoptotic protein HAX-1 form a chaperone complex that regulates sarcoplasmic reticulum (SR) calcium handling. With proteomic and genomic approaches, my lab is interested in identifying new regulators for calcium control and examining their shift of function in different diseased conditions. <br></p><p><strong>2. </strong><strong>Deciphering the crosstalk between calcium circuit and stress signaling pathways in diseased hearts.</strong> </p><p>Given the central role of calcium in regulating various cellular responses, it is important to understand how cardiac cells regulate local calcium signaling to activate signaling in the milieu without affecting other processes. Moreover, my works previously identified that SR calcium regulatory complex (PLN/SERCA/HAX-1) can crosstalk with endoplasmic reticulum (ER) stress response sensor, IRE-1. Disruption of this crosstalk is capable to sensitizing cardiac cell to cell death. Thus, one major research direction in my lab is to identify and understand novel crosstalk, which allows us to gauge the feasibility to simultaneously target two diseased mechanisms in failing hearts.<br></p><p><strong>3. </strong><strong>Understanding the mechanism of cardiotoxicity induced by current medication and identify therapeutic options.</strong></p><p>Cardiotoxicity, such as reduced cardiac function and induction of arrhythmia, is a major cause for drug withdrawal in the market. Furthermore, the application of promising treatment can be limited by black box warning with adverse cardiovascular complication. Classic examples are anthracycline and tyrosine kinase inhibitors, which are commonly used in cancer therapy. My lab is interested in identifying the cardiac-specific mechanisms induced by those agents. It will allow us to develop strategy to prevent the adverse side effects in the heart but retain the cancer killing property.<br></p> | | <p></p><p><strong>​Lam CK</strong>, Wu JC. Clinical Trial in a Dish: Using Patient-Derived Induced Pluripotent Stem Cells to Identify Risks of Drug-Induced Cardiotoxicity. Arteriorscler Thomb Vasc Biol. 2021 Mar;41(3):1019-1031</p><p>Feyen DA, McKeithan WL, Bruyneel AA, Spiering S, Hörmann L, Ulmer B, Zhang H, Briganti F, Schweizer M, Hegyi B, Liao Z, Pölönen R, Ginsburg KS, <strong>Lam CK</strong>, Serrano R, Wahlquist C, Kreymerman A, Vu M, Amatya PL, Behrens CS, Ranjbarvaziri S, Maas RG, Greenhaw M, Bernstein, Wu JC, Bers DM, Eschenhagen T, Metallo CM, Mercola MM. Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes. Cell Rep. 2020 Jul 21;32(3):107925</p><p>Rhee JW, Yi H, Thomas D, <strong>Lam CK</strong>, Belbachir N, Tian L, Qin X, Malisa J, Lau E, Paik DT, Kim Y, Choi BS, Sayed N, Sallam K, Liao R, Wu JC. Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cell Rep. 2020 Jul 14;32(2):107886</p><p>Lee J, Termglinchan V, Diecke S, Itzhaki I, <strong>Lam CK</strong>, Garg P, Lau E, Greenhaw M, Seeger T, Wu H, Zhang JZ, Chen X, Gil IP, Ameen M, Sallam K, Rhee J-W, Churko JM, Chaudhary R, Chour T, Wang PJ, Snyder MP, Chang HY, Karakikes I, Wu JC. Activation of PDGF Pathway Links LMNA Mutation to Dilated Cardiomyopathy. <em>Nature</em>. 2019 Aug;572(7769):335-340. </p><p><strong>Lam CK</strong>, Tian L, Belbachir N, Shrestha R, Ma N, Kitani T, Rhee JW, Wnorowski A, Wu JC. Identifying the Transcriptome Signatures of Calcium Channel Blockers in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. <em>Circ Res</em>. 2019 Jul 5;125(2):212-222.</p><p>Wu H, Yang H, Rhee JW, Zhang JZ, <strong>Lam CK</strong>, Sallam K, Chang ACY, Ma N, Lee J, Zhang H, Blau HM, Bers DM, Wu JC. Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. <em>Eur Heart J</em>. 2019 Dec 1;40(45):3685-3695.</p><p>Kitani T, Ong SG, <strong>Lam CK</strong>, Rhee JW, Zhang JZ, Oikonomopoulos A, Ma N, Tian L, Lee J, Telli ML, Witteles RM, Sharma A, Sayed N, Wu JC. Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer. <em>Circulation.</em> 2019 May 21; 139(21):2451-2465.</p><p> Zhang JZ, Termglinchan V, Shao NY, Itzhaki I, Liu C, Ma N, Tian L, Wang VY, Chang ACY, Guo H, Kitani T, Wu H, <strong>Lam CK</strong>, Kodo K, Sayed N, Blau HM, Wu JC. A Human iPSC Double-Reporter System Enables Purification of Cardiac Lineage Subpopulations with Distinct Function and Drug Response Profiles. <em>Cell Stem Cell</em>. 2019 May 2;24(5):802-811</p><p>Seeger T, Shrestha R, <strong>Lam CK</strong>, Chen C, Mckeithan WL, Lau E, Wnorowski A, McMullen G, Greenhaw M, Lee J, Oikonomopoulos A, Lee S, Yang H, Mercola M, Wheeler M, Ashley EA, Yang F, Karakikes I, Wu JC. A Premature Termination Codon Mutation of MYBP3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay. <em>Circulation</em>. 2019 Feb 5;139(6):799-811.</p><p>Ma N, Zhang J, Itzhaki I, Zhang SL, Chen H, Haddad F, Kitani T, Wilson KD, Tian L, Shrestha R, Wu H, <strong>Lam CK</strong>, Sayed N, Wu JC. Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. <em>Circulation</em>. 2018 Dec 4;138(23):2666-2681.</p><p>Garg P, Oikonomopoulos A, Chen H, Li Y, <strong>Lam CK</strong>, Sallam K, Perez M, Lux RL, Sanguinetti MC, Wu JC. Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant. <em>J Am Coll Cardiol</em>. 2018 Jul 3;72(1):62-75.</p><p><strong>Lam CK</strong>, Wu JC. Disease Modelling and Drug Discovery for Hypertrophic Cardiomyopathy Using Pluripotent Stem Cells: How Far Have We Come? <em>Eur Heart J.</em> 2018 Nov 14;39(43):3893-3895.</p><p> Liu GS, Gardner G, Adly G, Jiang M, Cai WF, <strong>Lam CK</strong>, Alogaili F, Robbins N, Rubinstein J, Kranias EG. A Novel Human S10F-Hsp20 Mutation Induces Lethal Peripartum Cardiomyopathy. <em>J Cell Mol Med</em>. 2018 May 15;22(8): 3911–3919.</p><p>Bidwell PA, Liu GS, Nagarajan N, <strong>Lam CK</strong>, Haghighi K, Gardner G, Cai WF, Zhao W, Mugge L, Vafiadaki E, Sanoudou D, Rubinstein J, Lebeche D, Hajjar R, Sadoshima J, Kranias EG. HAX-1 regulates SERCA2a oxidation and degradation<em>. J Mol Cell Cardiol</em>. 2017 Nov 21;114:220-233</p><p>Liu GS, Zhu H, Cai WF, Wang X, Jiang M, Essandoh K, Vafiadaki E, Haghighi K, <strong>Lam CK</strong>, Gardner G, Adly G, Nicolaou P, Sanoudou D, Liang Q, Rubinstein J, Fan GC, Kranias EG. Regulation of BECN1-Mediated Autophagy by HSPB6: Insights from A Human HSPB6S10F Mutant. <em>Autophagy</em>. 2017 Nov 20:1-56.</p><p>Liang P, Sallam K, Wu H, Li Y, Itzhaki I, Garg P, Zhang Y, Termglinchan V, Lan F, Gu M, Gong T, Zhuge Y, He C, Ebert A, Sanchez-Freire V, Churko J, Hu S, Sharma A, <strong>Lam CK</strong>, Scheinman M, Bers D, Wu JC. Patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes elucidate single cell phenotype of Brugada Syndrome. <em>J Am Coll Cardiol</em>. 2016 Nov 8;68(19):2086-2096.</p><p><strong>Lam CK</strong>, Zhao W, Liu G, Cai W, Gardner G, Adly G, Kranias EG. HAX-1 Is a New Regulator of Cyclophilin-D Levels and the Mitochondrial Permeability Transition Pore in the Heart. <em>Proc Natl Acad Sci USA</em>. 2015 Nov 24;112(47): E6466-75.</p><p>Pritchard TJ, Haghighi K, Singh VP, Bidwell P, Liu GS, <strong>Lam CK</strong>, Vafiadaki L, Das P, Florea S, Vanderbilt E, Rubinstein J, Hajjar RJ, Kranias EG. Human G109E-Inhibitor-1 Impairs Cardiac Function and Promotes Arrhythmias<em>. J Mol Cell Cardiol</em>. 2015 Dec;89(Pt B):349-59.</p><p>Cai W, Liu G, <strong>Lam CK</strong>, Florea S, Qian J, Zhao W, Pritchard T, Haghighi K, Lebeche D, Lu LJ, Deng J, Fan GC, Hajiar RJ, Kranias EG. Micro-RNA765 Targets Protein Phosphatase Inhibitor-1 and Suppresses Contractility. <em>Eur J Heart Fail.</em> 2015 Aug;17(8):782-93.</p><p>Liu G, Morales A, Vafiadaki E, <strong>Lam CK</strong>, Haghighi K, Adly G, Hershberger RE, Kranias EG. A Novel Human R25C-Phospholamban Mutation Is Associated with Superinhibition of Calcium Cycling and Ventricular Arrhythmia. <em>Cardiovasc Res</em>. 2015 Jul 1;107(1):164-74.</p><p><strong>Lam CK</strong>, Zhao W, Cai W, Vafiadaki E, Florea S, Ren XP, Liu Y, Robbins N, Zhang Z, Zhou X, Jiang M, Rubinstein J, Jones WK, Kranias EG. Novel Role of HAX-1 in Ischemic Injury Protection: Involvement of Hsp90. <em>Circ. Res</em>. 2013 Jan 4;112(1):79-89.</p><p>Cai W, Pritchard T, Florea S, <strong>Lam CK</strong>, Han P, Zhou X, Yuan Q, Lehnart SE, Allen PD, Kranias EG. Ablation of Junctin or Triadin Is Associated with Increased Cardiac Injury Following Ischaemia/reperfusion. <em>Cardiovasc Res</em>. 2012 May 1;94(2):333-41.</p><p>Han P, Cai W, Wang Y, <strong>Lam CK</strong>, Arvanitis DA, Singh V, Chen S, Zhang H, Zhang R, Chen H, Kranias EG. Catecholaminergic Induced Arrhythmias in Failing Cardiomyocytes Associated with Human HRCS96A Variant Overexpression. <em>Am J Physiol Heart Circ Physiol</em>. 2011 Oct;301(4):H1588-95.</p><p>Qian J, Vafiadaki E, Florea SM, Singh VP, Song W, <strong>Lam CK</strong>, Wang Y, Yuan Q, Pritchard TJ, Haghighi K, Rodriguez P, Wang HS, Sanoudou D, Fan GC, Kranias EG. Small Heat Shock Protein 20 Interacts with Protein Phosphatase-1 And Enhances Sarcoplasmic Reticulum Calcium Cycling. <em>Circ Res</em>. 2011 Jun 10;108(12):1429-38.</p><p>Wang HS, Arvanitis DA, Dong M, Niklewski PJ, Zhao W, <strong>Lam CK</strong>, Kranias EG, Sanoudou D. SERCA2a Superinhibition by Human Phospholamban Triggers Electrical and Structural Remodeling in Mouse Hearts. <em>Physiol Genomics</em>. 2011 Apr 12;43(7):357-64.</p><p>Goonasekera SA, <strong>Lam CK</strong>, Millay DP, Sargent MA, Hajjar RJ, Kranias EG, Molkentin JD. Mitigation of Muscular Dystrophy in Mice by SERCA Overexpression in Skeletal Muscle. <em>J Clin</em> <em>Invest.</em> 2011 Mar;121(3):1044-52.</p><p>Zhao W, Waggoner JR, Zhang ZG, <strong>Lam CK</strong>, Han P, Qian J, Schroder PM, Mitton B, Kontrogianni-Konstantopoulos A., Robia SL, Kranias EG. The Anti-apoptotic Protein HAX-1 Is a Regulator of Cardiac Function. <em>Proc. Natl Acad Sci USA.</em> 2009 Dec 8;106(49):20776-81.</p><p></p> | | <ul><li><a href="https://cklamlab.bio.udel.edu/">https://cklamlab.bio.udel.edu</a><br></li><li>​<a href="http://www.cklamlab.com/" target="_blank" data-saferedirecturl="https://www.google.com/url?q=http://www.cklamlab.com&source=gmail&ust=1592060105726000&usg=AFQjCNFp-uHKtZfF090sggtv1buGcj8Pmg">www.cklamlab.com</a><br></li></ul> | <img alt="Dr. Chi Keung Lam" src="/content-sub-site/PublishingImages/people/lamcg/Chi%20Keung%20Lam.jpeg" style="BORDER:0px solid;" /> | |
