The Foskett laboratory is interested in mechanisms of ion permeation across cell membranes and intracellular signaling, particularly in epithelial cells, and the roles of these processes in diseases, including cystic fibrosis. The lab has two distinct major foci of research efforts.
a) Cystic Fibrosis: Cystic fibrosis (CF) is the most common potentially lethal genetic disease among Caucasians. Although the spectrum of clinical manifestations is quite wide, an underlying basis of CF is abnormal regulation of ion and fluid transport by epithelial cells in organs which are severely affected in the disease, including the lungs, pancreas, reproductive tract and intestines. The CF gene product (CFTR) is a cAMP-regulated Cl- ion channel that is expressed in the apical membranes of epithelial cells. The Foskett lab’s research focuses on understanding the activities, regulation and roles of the normal and mutant cystic fibrosis gene product. The lab’s recent efforts have been on identifying proteins that interact with CFTR, and elucidating the consequences of these protein-protein interactions. The Lab hopes that by understanding the nature of the complex of proteins with which CFTR interacts, it may discover novel insights that could be exploited for therapeutic purposes. In the future, students and fellows in the lab could consider these research areas: developing genomic-scale approaches to discover therapeutic proteins in cells; developing physiological approaches to examine the functions of CFTR in intact tissues; and studying the single channel properties of CFTR to determine its oligomeric structure and to define the ion permeation pathway. The Lab’s research has been funded by grant support from the NIH and the Cystic Fibrosis Foundation.
b) Calcium signaling: The second focus of the group is understanding the molecular physiology of intracellular signaling by Ca2+, with a particular focus on unique approaches for studying the properties and regulation of intracellular Ca2+ release channels, especially inositol trisphosphate receptors, and their roles in normal and pathological cell physiological states. The inositol trisphosphate receptors are a family of proteins expressed in all cells, that participate in generating Ca2+ signals which can be manifested as highly localized subcellular events or more globally throughout cells, often as highly complex signals with exquisite patterns generated in both space and time. These signals participate in normal cell physiological processes, including mitosis, motility, secretion and gene transcription, and in pathological states, including epilepsy, Alzheimer's disease and programmed cell death (apoptosis). The Lab has developed novel techniques to study the properties of single inositol trisphosphate receptor ion channels, and it has recently developed new expression systems to enable the study of recombinant isoforms. An important goal is to relate the behaviors of the channels to the properties of the cytoplasmic Ca2+ signals that they generate. In addition, the Lab wishes to understand the molecular details involved in the regulation of channel gating activity. The Lab is also attempting to discover the molecular mechanisms that enable calcium signals to be highly localized in cells. In the future, students and fellows in the lab could consider these research areas: identifying protein complexes associated with the InsP3 receptor and analyzing the functional implications; investigating the structure-function relationships of the channel to determine how the channel is regulated and the mechanisms of ion permeation and channel gating; development of animal models. This research is funded by the NIH. Additional support to examine the roles of ion channels in apoptosis and AIDS has been provided by the Dept. Defense Breast Cancer Initiative and the Penn Center for AIDS Research.
The techniques the Foskett lab employs in the lab span the spectrum from biophysical to molecular. Biochemical and molecular tools are used within the context of physiological measurement, with the goal to understand how molecular behavior results in complex cell physiological processes in normal and disease states. The Lab employs electrophysiology, including single ion channel patch clamping and two-electrode voltage clamping; digital low light-level fluorescence imaging microscopy of single living cells; micro-injection; yeast 2-hybrid system to examine and discover protein interactions; recombinant protein expression; molecular biology; and biochemistry.