About Sickkids
About SickKids

Christine Bear, PhD

Research Institute
Senior Scientist
Molecular Structure & Function

University of Toronto
Professor
Physiology


Phone: 416-813-5981
Fax: 416-813-5028
e-mail: bear@sickkids.ca

For more information, visit:

Bear Lab website
Breathe

Research Interests

  • Ion channels and human disease
  • Epithelial tissue physiology
  • Electrophysiology
  • Cystic Fibrosis
  • Stroke

Research Activities

Studies of the Structural Architecture and Functional Properties of Chloride Channels

Chloride channels contribute to critical biological functions such as the regulation of electrical excitability in muscle and neurons, fluid transport in epithelial tissues and pH regulation in intracellular organelles. Mutations in genes which encode chloride channels lead to human diseases such as Congenital Myotonia, Cystic Fibrosis, Dent’s disease of the kidney and Congenital Osteopretosis. We are primarily interested in defining the molecular basis of the diseases that arise from mutations in specific chloride channel genes.

At present, our specific studies focus on understanding the molecular and structural basis for Cystic Fibrosis, the disease caused by mutations in the gene, CFTR. Our group developed the means for purification and functional reconstitution of the protein product of CFTR (Bear, C. et al. Cell 1992). Further, we showed in electrophysiological studies in planar lipid bilayers, that wild type CFTR functions as a chloride channel and as an ATPase and certain disease causing mutations in CFTR cause specific defects in these functions (Li, C. et al. Nature Genetics 1993) (Li, C. et al. J. Biol. Chem. 1996) (Pasyk, E. et al. J. Biol. Chem. 1998), (Kogan, I. et al. J. Biol. Chem. 2001). Recently, we have developed novel methods for assessment of the quaternary structure of CFTR in cell membranes obtained from native tissues and the separation and reconstitution of each structure (Ramjeesingh, M. et al., Biochem. J. 1999) (Ramjeesingh, M. et. al. Biochemistry, 2000) . We found that while monomeric CFTR is the minimal functional unit, the protein self-associates to form dimers at the plasma membrane. We are currently using our reconstitution system to determine the functional consequences of this self association and the impact of disease-causing mutations on this process.

According to studies by our group and other research groups, it is clear that the severity of Cystic Fibrosis relates not only to the molecular consequences of disease causing mutations but also to the function of "modifying" genes which may complement the chloride channel function CFTR (Rozmahel R. et al. Nature Genetics 1993) (Kent, G. et al. J. Clin. Invest. 1999). Recently, we have determined using immunofluorescence with confocal and electron microscopy that members of a large family of chloride channels, the ClC family of chloride channels are localized appropriately in the plasma membrane of epithelial cells and function as chloride channels at this site (Mohammad-Panah, R. et al. J. Biol. Chem., 2001) . At present, we are assessing the capacity of these other channels to functionally complement CFTR in CF-affected tissues. Furthermore, we are studying the biochemical and biophysical properties of these channels using the tools described in the preceding paragraphs. In fact, we have purified and functionally reconstituted monomeric, dimeric and tetrameric ClC-2 and determined that unlike CFTR, a dimer is the minimum functional unit of this channel forming protein (Ramjeesingh, M. et al. Biochemistry, 2000). Our long term goal is to obtain a high resolution structure of these chloride channels in order to confirm and define basic features, such as the quaternary structure, the channel pore and the basis for the interaction between the pore and regulatory domains.

Publications

A list of Dr. Bear's publications can be found at the Bear Lab website.

Intellectual Property

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein (US 5,543,399)