Heads of Laboratories
A cell’s ability to accurately segregate genetic material during division is essential for the survival of an organism, and errors can result in developmental defects and diseases. Dr. Kapoor’s laboratory takes a multidisciplinary approach to investigating the molecular and physical mechanisms that explain how exactly one copy of the genome is delivered to each daughter cell during cell division.
During cell division, the mitotic spindle — a transient, organizational state of the cytoplasm — converts chemical energy into mechanical energy for DNA transport. The entire process takes only minutes, and several of the steps occur within seconds. Dr. Kapoor is interested in the precise mechanisms of key steps of the process. His research can be divided into three areas: observing cell division, reconstituting division processes with purified components and perturbing division to examine its mechanisms.
Cell division involves the transport of chromosomes along tracks of tubulin polymers. This transport is driven by motor proteins, with signaling proteins regulating the direction and distance of movement. Dr. Kapoor uses state-of-the-art microscopy to follow, at the highest resolution possible, the dynamics of the cargo, the tracks, the motor proteins and the key regulators in single dividing cells. His live cell imaging methods (which include multimode real-time confocal, differential interference contrast, fluorescence resonance energy transfer, fluorescence recovery after photobleaching, photoactivation of fluorescence and fluorescence speckle microscopy) have allowed measurements of transport dynamics that provide the input needed to build quantitative models of cell division.
Another way to understand any biological process is to reconstitute it using individual components in vitro. During cell division, the microtubule tracks must be transported relative to each other and organized into a bipolar spindle, something that can be directly observed in vertebrate mitotic spindles. Dr. Kapoor has reconstituted the antiparallel sliding apart of microtubules using microtubules and pure recombinant Eg5 (kinesin-5), a widely conserved mitotic kinesin. This assay system is the first step toward an in vitro “minimal spindle” that the laboratory is using to test key models for the mitotic spindle’s assembly and function.
To perform these cell division studies, Dr. Kapoor has innovated several refinements in the use of cell-permeable, small organic molecules. These molecules allow researchers to intervene in cellular processes on a timescale of minutes to seconds and then reverse the intervention to examine how a cellular system recovers from the inhibition or activation of one of its components. The temporal control over protein function that this technique provides is particularly suited to studying the rapid process of cell division, and Dr. Kapoor has developed methods for the discovery, chemical synthesis and characterization of bioactive small molecules as well as assays that exploit the control over protein function that these small molecules provide.
Recent research from Dr. Kapoor’s lab, in which the scientists were able to manipulate chromosome positions in living cells using chemical probes, overturned a long-standing theory of cell division that stated that each chromosome must be bioriented, that is, attached to each end of the bipolar spindle, before congressing to the metaphase plate, the center of the cell division apparatus. Rather, high-resolution microscopy revealed that chromosomes can also hitchhike their way to the center by attaching to microtubules associated with already bioriented chromosomes, pushed along by a molecular motor. Further research into this molecular motor, called CENP-E, could lead to novel chemotherapies that interrupt mitosis in rapidly dividing, cancerous cells.
A deeper understanding of the cell division process can help in the development of better therapeutics for diseases associated with improper division. In addition, small-molecule probes that Dr. Kapoor and his lab members have identified can serve as templates for drugs and help validate new targets for chemotherapeutics.
Dr. Kapoor graduated from the California Institute of Technology with bachelor’s degrees in chemistry and biology in 1993. He received his Ph.D. in chemistry in 1998 from Harvard University and did his postdoctoral research at Harvard Medical School. He came to Rockefeller in 2001 as assistant professor and was named associate professor in 2005 and professor in 2008.
Dr. Kapoor received the 2012 Irving Sigal Young Investigator Award from The Protein Society and a Leukemia and Lymphoma Society Scholar Award in 2008. In 2003 he was named a Pew Fellow in the Biomedical Sciences.
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