A discovery of potential importance to cystic fibrosis therapy
Hidden signals in a well-studied gene
November 9, 2009 — For the past 20 years, regulatory mechanisms controlling a large gene that is
mutated in cystic fibrosis (CF) patients have eluded scientists. CF is a severe genetic disease that results
in lung damage and nutritional deficiencies. Mutations in the cystic fibrosis transmembrane conductance regulator
(CFTR) cause changes in the airway surface liquid that produce a thick mucus
layer. This results in colonization by
bacteria, which acquire antibiotic resistance and become increasingly difficult
to eradicate. Although treatments for CF
patients have improved, therapeutics that target the underlying CFTR defect
could make a major difference to the health and longevity of these individuals.
In a study published online on November 6, 2009, in the Proceedings of the National Academy of Sciences of the United States ofAmerica (PNAS), the laboratory of Ann Harris has found that the CFTR gene adopts a very specific three-dimensional conformation in cells that express the gene and thus are affected by the disease. In cell types where the gene is silent
this conformation does not exist. The genetic elements that coordinate this
conformation lie at large distances from each other, and thus the discovery and
characterization of these elements and the proteins that interact with them
will likely have important implications for CF therapeutics that aim to boost
expression of the gene in specific cell types, either by gene therapy or by pharmacological
methods. Moreover, this study offers a framework for the discovery of distal
genetic elements that regulate the expression of other disease-causing genes.
The
first author is Christopher Ott, a graduate student in the Harris laboratory
and a member of the Integrated Graduate Program in the Life Sciences (IGP) at Northwestern University. The other authors in the Harris laboratory
are Neil Blackledge, a former graduate student and postdoctoral fellow; Jenny Kerschner, IGP graduate student; and Shih Hsing
Leir, postdoctoral fellow. Collaborators
are Dr. Greg Crawford of Duke University and Dr. Calvin Cotton of Case Western
University. Ann Harris, PhD, is Professor of Pediatrics
and the Valerie and George D. Kennedy Endowed Chair in Human Molecular
Genetics, Northwestern University’s Feinberg School of Medicine; and the
director of the Human Molecular Genetics Program of Children’s Memorial Research Center.
Children’s Memorial Research Center is the research arm of Children's Memorial
Hospital, the pediatric teaching hospital for Northwestern
University's Feinberg School of Medicine. The research center is also one of 29
interdisciplinary research centers and institutes of the Feinberg School,
where principal investigators who are part of the research center are full-time
faculty members. Built upon a team approach, the research center
generates knowledge that will lead to cures for the diseases of children with
additional focus on the pediatric precursors of adult diseases. The
research center actively encourages a synergy of ideas among physician
scientists, basic scientists, technicians, nurses and trainees in various
disciplines. Its thematic research programs bridge gaps between the
biomedical, clinical and social sciences and provide an environment to
accomplish common goals.
For more information contact Peggy Jones, Children’s Memorial Research Center
at 773.755.6341 or pmjones@childrensmemorial.org.