Megan and Erik to present at Student Seminar on 5.28.09

Megan Ealy and Erik Westin will be presenting Student Seminar this week in CBRB 2289 at noon. In keeping with Erik’s tradition, I have asked the speakers to provide a brief overview for their talks. Hope to see you there!

Background for Megan’s talk

Otosclerosis is one of the most common forms of adult onset hearing loss. The disease involves abnormal bone remodeling of the otic capsule. When bony lesions encroach on the stapes a conductive hearing loss occurs. The disease is prevalent in 0.3-0.4% of the Caucasian population. While environmental as well as genetic factors are suggested to play a role in the disease, the etiology remains poorly understood. To determine genetic components of otosclerosis, we have performed a genome-wide association study that identified association with the RELN locus in Belgian-Dutch and French populations. We were also able to demonstrate expression of RELN in mouse inner ear and human stapes footplate samples. We have replicated this association is several additional European populations. In addition we are working to identify regulatory elements that regulate genes that we have shown to be differentially expressed in otosclerosis via a microarray analysis of human stapes footplates. Functional analysis of these genes associated with otosclerosis will help us better understand the pathophysiology of the disease.

Background for Erik’s talk

westin_SSTwo known molecular mechanisms by which cells age are through telomere attrition and the accumulative effects of free radical damage from oxidative stress.  Telomere attrition takes place under routine growth conditions but can be accelerated by elevated oxidative stress.  Excessive telomere attrition is a hallmark found in patients with Dyskeratosis congenita (DC; OMIM) due to mutations in telomerase complex genes and concomitant diminished telomerase activity.  DC is associated with a variety of clinical symptoms including skin dyspigmentation, leukoplakia, dyskeratotic nails, and an increased susceptibility to cancer and bone marrow failure.  Our laboratory has characterized cells acquired from affected members of an autosomal dominant multi-generation DC kindred with a deletion in the 3’ terminus of the TERC gene.  Fibroblasts, lymphocytes, and keratinocytes from these donors have very short telomeres and decreased proliferative potential.  In this study, we demonstrate a novel increase in parameters indicative of oxidative stress levels in DC cells. This increase is ameliorated upon telomerase mobilization and is dependent on the telomere elongation function of telomerase rather than other proposed telomerase properties. In addition, targeted down-regulation of specific cellular transcripts by shRNA or exogenous expression of cDNA involved in mitigating oxidative stress are capable suppressing oxidative stress parameters.  Our data supports a model whereby telomere attrition initiates a signaling cascade leading to activation of specific DNA damage and cell stress responders.  These findings offer an additional mechanism to explain how telomere attrition may lead to cellular aging and senescence.

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Posted on May 25, 2009, in Student Seminar and tagged , , , , , , , , . Bookmark the permalink. Leave a comment.

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