Coordinated Doctoral Program Blends Backgrounds and Perspectives to Create Unique Training Environment
By Richard B. Robinson, Ph.D., Associate Dean for Graduate Affairs

The Coordinated Doctoral Program in the Basic Sciences, established at CUMC in 1998, is not a degree-granting program but an organizational and oversight structure that fosters interaction and coordination and maintains quality control among the 10 degree-granting doctoral programs in the biomedical sciences.
   The Coordinated Program works with the individual graduate programs to identify and organize useful common courses. It also ensures maximal flexibility for students in their selection of laboratories for research rotations and thesis research. Students can conduct thesis research with faculty affiliated with any of the programs, not just those of their home program. As a result, one now frequently finds students from several different doctoral programs working side by side in the same laboratory on related projects.
   This broadens the perspective and experience of graduate students and can facilitate collaborations and interactions among laboratories in different departments. One example of a laboratory where this sort of cross-fertilization occurs is that of Robert S. Kass, Ph.D., professor and chairman of pharmacology.
   Dr. Kass’ laboratory studies the regulation of ion channel expression and function in normal and genetically altered cardiac cells with the objective of elucidating the fundamental mechanisms that underlie sudden cardiac death. The research involves multidisciplinary and collaborative studies that include structural biology, electrophysiology, molecular biology, and genetics. Students in the laboratory benefit from exposure to this multidisciplinary approach, either within their own research or from the interactions that occur among students taking different approaches to answering the same basic scientific questions.
   Currently, five students from four Ph.D. programs are conducting their thesis research in Dr. Kass’ laboratory. Ian
The Kass Lab
The Kass Lab
Front: R.S. Kass and Priscilla Chan
Middle row (seated): John Bankston, Kevin Sampson, and Cecile Terrenoire
Back: David Malito, David Chung, Nicolas Lindegger, Lei Chen, and Suneel Kateriya
Glaaser and Priscilla Chan are both pharmacology students (in their fifth and second years, respectively). John Bankston is a fourth-year physiology student, David Chung an M.D./Ph.D. student in the third year of his Ph.D. studies through the integrated graduate program in cellular, molecular and biophysical studies, and David Malito a second-year neurobiology student.
   Both Ian and John are studying structure-function aspects of the cardiac sodium channel and the influence of mutations known to occur in certain inherited cardiac arrhythmias, but they are taking complementary approaches. Ian is working on a project designed to determine the structural basis of an intramolecular complex that controls inactivation gating of the channel. His work, which is being conducted in collaboration with the laboratory of Lawrence Shapiro, Ph.D., (biochemistry and molecular biophysics and ophthalmology) will provide insight into the molecular basis of arrhythmias caused by inherited mutations in the gene that codes for this channel as well as into novel molecular targets that may be used to control or prevent these electrical disturbances. He works with both known disease mutations and mutations or residues that were predicted to be critical to putative channel structures based on homology modeling.
   Mutations identified in this way are often further investigated by John, who is studying the functional consequences of mutations in the region of the heart sodium channel that Ian characterizes at the atomic level. John’s work will, at the level of single sodium channel recordings, provide an understanding of how intramolecular interactions in the sodium channel change the ability of the channel to open and/or transition into nonconducting inactivated states.
   While Ian and John are focused on the pore forming subunit of the cardiac Na channel, David Chung and Priscilla Chan have been studying a K channel and related protein-protein interactions.
   David’s project focuses on determining how the two subunits of a key cardiac potassium channel interact, where they interact, and how these interactions control channel gating. This channel, referred to as IKs, consists of a pore forming alpha subunit (KCNQ1) and an auxiliary beta subunit (KCNE1). Disruption of proper subunit interactions and/or structure can result in increased likelihood of arrhythmia and sudden cardiac death. David’s project, like Ian’s, is collaborative. It includes key contributions from Arthur Karlin, Ph.D. (biochemistry and molecular biophysics, neurology, and physiology and cellular biophysics) and Steven Marx, M.D. (medicine and pharmacology). David introduces single cysteine mutations into specific locations of both the beta and alpha subunits and then uses chemical cross-linking of these cysteines to obtain a physical map of the interactions between the subunits. He also uses patch clamp analysis to identify any functional consequences of the interactions.
   Priscilla is just beginning her work in the laboratory. During her rotation in the laboratory last year, she worked with David on subunit interactions in the IKs channel. She now is beginning to design optical reporters for protein-protein interactions, which she plans to use to complement this earlier work. She will fluorescently tag the KCNQ1 and KCNE1 proteins and use FRET or a novel imaging technique, a protein complementation assay, to study the interactions and determine whether PKA-dependent phosphorylation of the channel alters the intermolecular interactions of these subunits.
   David Malito also is just beginning his thesis research, working on a project designed to study the unique pharmacological and biophysical properties of Cav1.2 calcium channels harboring an inherited mutation (Timothy syndrome mutation). This mutation is causally related to the Long QT syndrome, a disorder that also can be caused by mutations in the IKs potassium channel or the Nav1.5 sodium channel described above. In the case of the Timothy syndrome mutation, the mutant channels lack the naturally occurring mechanism of inactivation that normally limits calcium entry during a single cardiac action potential. The mutant channels thus provide the unique opportunity to study the pharmacology of inactivation-deficient calcium channels. These experiments, if successful, will complement previous work in the Kass laboratory in which mutation-specific pharmacological profiles of mutant channels, associated with inherited human cardiac arrhythmias, have been defined.
   The students agree that their diversity of background before graduate school, rather than the fact that they are enrolled in different graduate programs, has had the greatest effect on their personal perspective and research direction. Although each program monitors the progress of its own students during thesis research, the students feel that their individual programs are transparent within the lab environment because of the many common core elements and the interactions fostered by the coordinated program. Since the programs draw students with different backgrounds, experiences, and interests, working together provides breadth in perspective that would otherwise be lacking. For example, David Chung and David Malito were undergraduate chemistry and physics majors, respectively, while John Bankston earned his undergraduate degree in biomedical engineering, and Ian Glaaser and Priscilla Chan received degrees in molecular biology. These varieties in background influenced their selection of individual research projects and approaches, but the interactions within the laboratory are clearly synergistic and enhance the experience and thesis training of all involved.

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