Research Interests:
The role of human genetic variability in response to pharmaceuticals
or xenobiotics (commonly referred to as pharmacogenomics and toxicogenomics,
respectively) is a burgeoning field of study. However, the
ability to study the function of a single gene under normal or disease
states is hampered by the large interindividual variability found
in the human population. To control for environmental and
genetic effects, we can use inbred genetically-engineered mice to
study human gene function in vivo.
Through gene targeting in embryonic stem cells and various transgenic
methodologies, it is possible to develop mice with specific gene
deletions and/or express any chosen gene of interest in a defined
temporal and spatial pattern. Current projects under investigation
in my laboratory include:
1) The role
of the ABC transporter MDR1 in a mouse model of inflammatory bowel
disease. Epidemiological studies have linked the MDR1 gene
with increased risk of Crohn’s disease and unlcerative colitis
and mice with a targeted deletion of Mdr1a
spontaneously develop inflammatory bowel disease.
2) Generation
of Cre-recombinase transgenic mouse lines that will allow CNS-specific
gene disruption (e.g., to reduce P-glycoprotein expression at the
blood-brain and blood-CSF barriers). The penetrance of drugs
into the CNS is tightly regulated by transporters at brain endothelial
junctions including P-glycoprotein-the ability to disrupt this activity
in a CNS-specific manner while maintaining function in other tissues
will be of great utility in evaluating drugs targeting the brain.
3) Development
of a Cyp4b1 knockout
mouse to study the physiological role of this gene and its function
in xenobiotic bioactivation. CYP4B1 cloned and expressed from
a variety of different species bioactivates arylamine xenobiotics
and may play a role in oxidation of endogenous fatty acids such
as arachidonic acid and the leukotrienes. The functional activity
of the human form however, is unknown due to the inability to express
the enzyme in vitro. Expressing human CYP4B1 in a Cyp4b1
knockout mouse will address the endogenous function of the murine
gene and functionality of the human enzyme.
Biography:
Dr. Kelly earned his Ph.D. in Biochemistry from the University
of Washington in 1996. Following a post-doctoral fellowship in molecular
toxicology in the Department of Environmental Health at the University
of Washington, he worked at Targeted Genetics evaluating the safety
and efficacy of gene therapies. He has served as the manager of
the Center for DNA Sequencing and Gene Analysis in the School of
Pharmacy (http://depts.washington.edu/pceut/pceut_services/index.html)
since 2003, and was appointed to the position of Acting Assistant
Professor in April 2006.
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