Michael Kotlikoff, VMD, PhD
The Kotlikoff laboratory focuses on the molecular processes underlying cardiovascular development, function, and dysfunction. We focus on two general areas: the development of genetic optical sensors and effectors for in vivo molecular physiology; and the study of repair processes within the damaged heart, including the role of cardiovascular and vascular progenitors and cell-based therapies.
Development and application of optical tools for in vivo imaging at molecular scale
The Kotlikoff lab published the first use of genetically encoded sensors for in vivo measurements in mice.This development was made possible by collaboration with the laboratory of Junichi Nakai who developed the original GFP-based Ca2+ sensor, GCaMP. That sensor misfolded at body temperature and could only be used for ex vivo measurements at room temperature. Our lab worked to introduce multiple stabilizing mutations leading to the development of GCaMP2 and the exciting demonstration of lineage specific cardiac imaging in mice in vivo, in real time, allowing us to explore and understand embryonic heart development.Since that time, the use of genetically encoded sensors and optogenetic molecules has increased dramatically, leading to the establishment of an NIH funded resource, CHROMusTM (http://chromus.vet.cornell.edu/), in 2014. CHROMusTM, under the direction of Dr. Kotlikoff, is in the midst of developing fifty transgenic mouse lines designed for combinatorial crosses enabling the co-expression of rhodopsin based effectors and red and green Ca2+ sensors in interacting lineages. We use lineage -targeted BAC transgenics, and novel combinations of sensors and effectors to create these mouse lines, and distribute them around the country and world, allowing researchers to lead the discovery of novel physiology processes in the heart, brain, lung and immune systems. The resource enables these researchers to conduct experiments not otherwise possible in a cost effective and highly efficient manner, facilitating the use of optical genetic tools and markedly accelerating scientific discovery.
Molecular Processes Underlying Cardiac Development and Repair:
The Kotlikoff laboratory first identified the presence of c-kit positive cells in the neonatal heart and their unique developmental potential at that stage, and contrasted that potential with adult c-kit positive cells. At the early post-natal stage, these cells undergo myodifferentiation and heart repair. Following this period of post-natal heart development, c-kit positive cells adopt only vascular lineages and drive neovascularization. The laboratory has shown definitively that these cells are endogenous to the adult heart (do not arise from circulating endothelial cell precursors) and cannot adopt cardiac fates. By contrast, neonatal precursors are not committed to cardiac fates, but undifferentiated c-kit+ cells from the neonate are capable of adopting such fates in vitro, in explants to scid mice, and when transplanted to adult hearts.
Understanding stem cell therapy in the heart
The Kotlikoff laboratory has been focused for many years on understanding the limits and potential of exogenous cell therapy in the heart. Key early experiments in collaboration with Bernd Fleischmann’s lab identified the mechanism underlying arrhythmogenic activity of integrated skeletal myoblasts and the key determinants required for electrical coupling that dramatically lowers post-infarction arrhythmogenic risk. Connexin43 was determined to be essential for electrical coupling and arrhythmia risk reduction, as transgenic expression of this molecule to skeletal myoblasts conveyed protection.Subsequent experiments with Chuck Murry’s group demonstrated similar effects using differentiated, human ES cells in larger mammals.Recent experiments have identified the potential for gene based therapy using Connexin43 to promote heterogenous cell-cell coupling within the infarct of healing hearts.
Molecular Calcium Release Mechanisms
The Kotlikoff lab worked for many years on the molecular basis of Ca2+ release in muscle. In cardiac muscle the lab determined of the role of ryanodine receptor proteins (RYR2) in cardiac muscle Ca2+ release and demonstrated Ca2+ -induced Ca2+ release in smooth muscle. The latter was shown to result from “loose coupling” between voltage dependent Ca2+ channels and RYR2 receptors.Coupling mechanisms were also determined between stretch of smooth muscle and Ca2+. These early experiments were the first to explicitly define the role of RYR2 in cardiac and smooth muscle Ca2+ release.
- PhD, Physiology, University of California, Davis, 1984
- VMD, University of Pennsylvania, 1981
- BA, University of Pennsylvania, 1973
Michael I. Kotlikoff, professor of molecular physiology, became the 16th provost of Cornell University on August 1, 2015. A member of the Cornell faculty since 2000, he most recently served as the Austin O. Hooey Dean of Veterinary Medicine.
As dean (2007–2015), Kotlikoff initiated a comprehensive strategic plan to enhance the College of Veterinary Medicine’s programs in education, delivery of animal health care, and research, and he launched an $87 million capital project to upgrade infrastructure and teaching facilities and enable an increase in the pre-clinical class size. Throughout his tenure he oversaw an increase in diversity of the faculty, staff, and college administration; the expansion of clinical training opportunities for veterinary students; and a reorganization of the Cornell University Hospital for Animals. He also focused on expanding basic and clinical research programs and promoting translational linkages and interdisciplinary research.
Kotlikoff was recruited to Cornell in 2000 from the University of Pennsylvania, where he was Professor and Chair of the Department of Animal Biology, to become founding chair of the Department of Biomedical Sciences and chair of the Mammalian Genomics Life Science Initiative. He established and served as the first director of the Cornell Core Transgenic Mouse Facility and has served on or chaired many university committees, including the Local Advisory Committee of the Faculty, the Institute for Biotechnology and Life Science Technologies Scientific Advisory Committee, the Provost’s Graduate Field Task Force, and the Provost’s Budget Model Task Force, as well as numerous NIH committees and editorial boards.
The Kotlikoff research laboratory, which has been continuously funded by the NIH for over 30 years, is internationally recognized in the area of cardiovascular biology. As provost, Kotlikoff continues to maintain his laboratory.
Kotlikoff received his B.A. (literature) and V.M.D. degrees from the University of Pennsylvania and his Ph.D. in Physiology from the University of California, Davis.
- Chen L, Song H, Wang Y, Lee JC, Kotlikoff MI, Pritchard TJ, Paul RJ, Zhang J, Blaustein MP. Arterial α2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2 mice. Am J Physiol Heart Circ Physiol. 2015 Sep;309(5):H958-68.
- Shui B, Lee JC, Reining S, Lee FK, Kotlikoff MI. Optogenetic sensors and effectors: CHROMus-the Cornell Heart Lung Blood Institute Resource for Optogenetic Mouse Signaling. Front Physiol. 2014 Nov 6;5:428
- Tallini YN, Greene KS, Shui B, Russell CW, Lee JC, Doran RM, Nakai J, Kotlikoff MI. Genetically encoded probes provide a window on embryonic arrhythmia.Methods Mol Biol. 2014;1092:195-219.
- Hesse, M, A Raulf, G Pilz, C Haberlandt, AM Klein, R Jabs, H Zaehres, CJ Fugemann, K Zimmermann, J Trebicka, A Welz, A Pfeifer, W Roll, MI Kotlikoff C Steinhauser, M Gotz, HR Scholer, and BK Fleischmann. Direct visualization of cell division using high-resolution imaging of M-phase of the cell cycle. Nature Communications 2012;3:1076.
- Jesty, SA, MA Steffey, FK Lee, M Breitbach, M Hesse, S Reining, JC Lee, RM Doran, AY Nikitin, BK Fleischmann, and MI Kotlikoff. Cardiovascular precursors support postinfarction myogenesis in the neonatal, but not the adult, heart. Proc Natl Acad Sci. USA, 109:13380-13385, 2012.
- Shiba, Y, S Fernandes, WZ Zhu, D Filice, V Muskheli, J Kim, NJ Palpant, J Gantz, KW Moyes, H Reinecke, BV Biber, T Dardas, JL Mignone, A Izawa, R Hanna, M Viswanathan, JD Gold, MI Kotlikoff, N Sarvazyan, MW Kay, CE Murry, and MA Laflamme. Human ESCderived cardiomyocytes electrically integrate and suppress arrhythmias in injured hearts. Nature 1038:11317, 2012.
- Sonkusare, SK, AD Bonev, J Ledoux, MI Kotlikoff, DC HillEubanks, MT Nelson. Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336:597601, 2012.
- Shui, B, A Ozer, W Zipfel, N Sahu, A Singh, J Lis, H Shi, MI Kotlikoff. RNA Aptamers that Functionally Interact with Green Fluorescent Protein and Its Derivatives. Nucleic Acids Res 40:e39, 2012.
- Shui B, Q Wang, F Lee, LJ Byrnes, DM Chudakov, SA Lukyanov, H Sondermann, MI Kotlikoff. Circular permutation of red fluorescent proteins. PLoS One 6(5):e20505, 2011.
- Tallini, Y, KS Greene, M Craven, A Spealman, M Hesse, J Smith, A Woods, B Singh, A Yen, B Fleischman, and MI Kotlikoff. ckit+ precursors in the neonatal heart specify all cardiac lineages. Proc Natl Acad Sci 106:180813, 2009.
- Wang, Q, B Shui, MI Kotlikoff, H Sondermann. Structural basis for calcium sensing by GCaMP2. Structure 16:18171827, 2008.
- Tallini, YN, JF Brekke, B Shui, R Doran, SM Hwang, J Nakai, G Salama, S Segal, MI Kotlikoff. Propagated endothelial Ca2+ waves and arterioloar dilation in vivo: measurements in Cx40BACGCaMP2 transgenic mice. Circ Research 101:13001309, 2007.
- Roell, W, T Lewalter, BR Choi, BR, YN Tallini, T Bostani, U Becher, P Sasse, SM Hwang, R Doran, M Breitbach, S Reining, B Gabris, A Welz, G Salama, JW Schrickel, MI Kotlikoff, BK Fleischmann. Engraftment of electrically coupled cells in the heart prevents post infarct ventricular arrhythmias. Nature 450:819824, 2007.
- Kotlikoff MI. Genetically encoded Ca2+ indicators: using genetics and molecular design to understand complex physiology. J. Physiol. 578:5567, 2007
- Tallini, NY, M Ohkura, BR Choi, G Ji, K Imoto, R Doran, J Lee, P Plan, J Wilson, HB Xin, A Sanbe, J Gulick, J Robbins, G Salama, J Nakai, and MI Kotlikoff. Imaging Cellular Signals in the Heart in Vivo: Cardiac expression of the high signal Ca2+ indicator GCaMP2. Proc Natl Acad Sci 103:47534758, 2006.
- Xin, HB, KY Deng, B Shui, S Qu, Q Sun, J Lee, KS Greene, J Wilson, Y Yu, M Feldman, and MI Kotlikoff. Gene trap and gen inversion methods for conditional gene inactivation in the mouse. Nucleic Acids Research, 33:e14,110 2005.
- Xin, HB, T Senbonmatsu, D Cheng, YX Wang, J Copello, G Ji, ML Collier, KY Deng, LH Jeyakumar, MA Magnuson, T Inagami, MI Kotlikoff, and S Fleischer. Estrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature, 416:334337, 2002.
Awards and Honors
- 1973, B.A. magna cum laude, University of Pennsylvania
- 1979, Elected to Phi Zeta Honor Society
- 1981, Graduated 1(106), summa cum laude, Veterinary School
- 1981, J.B. Lippincott Prize, highest scholastic average in Veterinary School
- 1992, Hildegaard Doerenkam-Gerhard Zbinden International Research Prize - 2nd Prize
- 1995, Medal of Honor, Tohoku University, Japan
- 2002, Annual Smooth Muscle Lecture, Physiological Society
- 2004, Annual Totman Lecturer, University of Vermont
- 2005, Co-Organizer, FASEB Smooth Muscle Conference
- 2005, New and Notable Lecturer, Biophysical Society
- 2007, State of the Art Speaker, National Merck-Merial Summer Scholars conference
- 2008, Organizer, FASEB Smooth Muscle Conference
- 2008, Annual James O. Davis Lecture University of Missouri
- 2008, Alumnus of the Year Award, University of California, Davis, College of Veterinary Medicine
- 2009, Nobel Symposium Speaker – Fluorescent Protein
- 2010, Board of Scientific Counselors, National Heart, Lung, and Blood Institute, National Institutes of Health
- American Physiological Society
- Association for the Advancement of Science
- Biophysical Society
- Physiological Society of Philadelphia
- American Veterinary Medical Association
- American Lung Association
- American Association of Chairs of Physiology
- Society of General Physiologists
- American Society for Biochemistry and Molecular Biology