Chien Ho-Department of Biological Sciences - Carnegie Mellon University

Chien Ho

Professor

Address:
649 Mellon Institute
Department of Biological Sciences
Carnegie Mellon University
4400 Fifth Avenue
Pittsburgh, PA 15213
Phone: 412-268-3395
Fax: 412-268-7129

Education

Ph.D., Yale University
Postdoctoral Appointment, Massachusetts Institute of Technology

Research

Chien Ho currently has two well-established research programs.

The goal of research project (1) is to find the molecular basis/mechanism for the cooperative oxygenation of hemoglobin (Hb) by using multi-nuclear nuclear magnetic resonance (NMR) and other biochemical-biophysical techniques to investigate the structural, dynamic, and functional features of the Hb molecule. He has been a pioneer in applying NMR spectroscopic techniques to correlate the structure-function relationship in Hbs, and the first one to make use of human mutant Hbs for his research. His research has produced novel insights into communication between ligand-binding sites and has laid the foundation for understanding the molecular basis for both the alkaline and acid Bohr effects of hemoglobin. Another innovation of Ho’s research comes from his focus on questions of mechanisms of allostery that are required for hemoglobin function. His research has provided definitive evidence that the classic two-structure model taught to all students of molecular biology, biochemistry, and biophysics fails to describe the essential mechanistic as well as structural and dynamic aspects of oxygen binding. Rather an intricate web of multiple and highly specific interactions is required for Hb function. An important implication of this research is that allosteric interactions in other regulatory proteins and enzymes will also require multiple pathways for signal communication. Indeed, the “two-structure”-type models have now been replaced with this richer, more complex model of interactions. His Hb research also has the potential to provide a new approach to design a new generation of hemoglobin-based oxygen carriers (blood substitutes) and resuscitation fluids for treatment of traumatic brain injury plus hemorrhagic shock. His laboratory designed an expression plasmid to produce authentic Hb and any desired mutations in E. coli. He has sent his Hb expression plasmids to over 80 researchers worldwide who need them for their Hb research. He recently participated with an international team of scientists to resurrect an important protein, hemoglobin, from woolly mammoth, using his Hb expression plasmid.

The goal of research project (2) is to develop a novel magnetic resonance imaging (MRI) methodology to monitor immune response in vivo using rat models for cardiac transplant rejection. The immediate objective is to use rat allograft models to develop methods of cellular and functional MRI to monitor the infiltration of immune cells into the transplanted heart and to monitor the function of the transplanted heart in the same animal, and thereby detecting the early signs of acute and chronic rejection following heart transplantation. When organ rejection occurs, immune cells accumulate at the rejecting heart. MRI contrast agents, e.g., superparamagnetic iron-oxide particles, can be incorporated into rat macrophages and/or T-cells by phagocytosis/endocytosis. These particles and/or labeled cells can be introduced intravenously into the transplanted rats to monitor the accumulation of immune cells at the site of graft rejection. In the early 1990s, we were among the pioneers to develop MRI methods to monitor cell migration. In the early 2000, he and his colleagues were the first to monitor kidney, lung, and heart rejection in rat models by tracking the infiltration of microphages to the rejecting allograft organs by MRI.

Publications

Yeh FC, Ye Q, Hitchens TK, Wu YL, Parwani AV, Ho C. Mapping stain distribution in pathology slides using whole slide imaging. J Pathol Inform. 2014 Jan 31;5:1

Hitchens TK, Liu L, Foley LM, Simplaceanu V, Ahrens ET, Ho C. Combining perfluorocarbon and superparamagnetic iron-oxide cell labeling for improved and expanded applications of cellular MRI. Magn Reson Med. 2014 Jan 29.

Yuan Y, Byrd C, Shen TJ, Simplaceanu V, Tam TC, Ho C. Role of β/δ101Gln in regulating the effect of temperature and allosteric effectors on oxygen affinity in woolly mammoth hemoglobin. Biochemistry. 2013 Dec 10;52(49):8888-97.

Liu L, Hitchens TK, Ye Q, Wu Y, Barbe B, Prior DE, Li WF, Yeh FC, Foley LM, Bain DJ, Ho C. Decreased reticuloendothelial system clearance and increased blood half-life and immune cell labeling for nano- and micron-sized superparamagnetic iron-oxide particles upon pre-treatment with Intralipid. Biochim Biophys Acta. 2013 Jun;1830(6):3447-53.

Yuan Y, Shen T-J, Gupta P, Ho NT, Simplaceanu V, Tam TCS, Hofreiter M, Cooper A, Campbell KL and Ho C. A Biochemical-Biophysical Study of Hemoglobin from Wooly Mammoth, Asian Elephant, and Humans. Biochemistry 50, 7350-7360, 2011.

Wu, YJL, Ye Q, Ho C. Cellular and Functional Imaging of Cardiac Transplant Rejection. Current Cardiovascular Imaging Reports, 4, 50-62, 2011.

Chen C-L, Zhang H, Ye Q, Hsieh W-Y, Hitchens TK, Shen H-H, Liu L, Wu Y-J, Foley LM, Wang S-J, and Ho C. A New Nano-Sized Iron Oxide Particle with High Sensitivity for Cellular Magnetic Resonance Imaging. Molecular Imaging & Biology, D01.10.1007/s11307-010-0430-x, published on-line 24 September 2010.

Campbell KL, Roberts JEE, Watson LN, Stetefeld J, Sloan AM, Signore AV, Howatt JW, Tame JRH, Rohland N, Shen T-J, Austin JJ, Hofreiter M, Ho C, Weber RE, Copper A. Substitutions in Woolly Mammoth Hemoglobin Confer Biochemical Properties Adaptive for Cold Tolerance. Nature Genetics 42, 536-540, 2010.

Ho C and Yue Y. "Haemoglobin: Cooperativity in Protein-Ligand Interactions” (version 2.0) in Encyclopedia of Life Sciences, John Wiley & Sons, Ltd., Chichester http://www/els.net, April 2010.

Yuan Y, Simplaceanu V, Ho NT and Ho C. An Investigation of the Distal Histidyl H-bonds in Oxyhemoglobin: Effects of Temperature, pH, and Organic Phosphate. Biochemistry 49, 10606-10615 (2010). Selected by the Library of Faculty of 1000

Wu YL, Ye Q, Sato K, Foley LM, Hitchens TK, Ho C. Non-invasive Evaluation of Cardiac Allograft Rejection by Cellular and Functional MRI. Journal of the American College of Cardiology: Cardiovascular Imaging 2, 731-741, 2009.

Ye Q, Wu Y-JL, Foley LM, Hitchens TK, Eytan DF, Shirwan H and Ho C. Longitudinal Tracking of Recipient Macrophages in a Rat Chronic Cardiac Allograft Rejection Model with Noninvasive Magnetic Resonance Imaging Using Micrometer-Sized Paramagnetic Iron Oxide Particles. Circulation 118:149-156, 2008.

Song XJ, Simplaceanu V, Ho NT and Ho C. Effector-Induced Structure Fluctuation Regulates the Ligand Affinity of an Allosteric Protein: Binding of Inositol Hexaphosphate Has Distinct Dynamic Consequences for the T and R States of Hemoglobin. Biochemistry 47:4907-4915, 2008.

Maillett DH, Simplaceanu V, Shen T-J, Ho NT, Olson JS and Ho C. Interfacial and Distal Pocket Mutations Exhibit Additive Effects on the Structure and Function of Hemoglobin. Biochemistry 47, 10551-10563, 2008. PMC2692483

Shen T-J, Rogers H, Yu X, Lin F, Noguchi CT and Ho C. Modification of Globin Gene Expression by RNA Targeting Strategies. Experimental Hematology 35, 1209-1218, 2007.

Sahu SC, Simplaceanu V, Gong Q, Ho NT, Tian F, Prestegard JH and Ho C. Insights into the Solution Structure of Human Deoxyhemoglobin in Absence and Presence of an Allostertic Effector. Biochemistry 46, 9973-9980, 2007.

Gong Q, Simplaceanu V, Lukin JA, Giovannelli JL, Ho NT and Ho C. Quaternary Structure of Carbonmonoxyhemoglobins in Solution: Structural Changes Induced by the Allosteric Effector, Inositol Hexaphosphate. Biochemistry 45, 5140-5148, 2006.

Wu YL, Ye Q, Foley LM, Hitchens TK, Sato K, Williams JB and Ho C. In Situ Labeling of Immune Cells with Iron Oxide Particles: An Approach to Detect Organ Rejection by Cellular MRI. Proceedings of National Academy Sciences USA 103:1852-1857, 2006.

Lukin JA, Kontaxis G, Simplaceanu V, Yuan Y, Bax A and Ho C. Quaternary Structure of Hemoglobin in Solution. Proceedings of the National Academy of Sciences, U.S.A. 100:517-520, 2003.

Full PubMed Listings

Virtual Tour

Watch Dr. Ho describe the research completed within his laboratory and more.