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Nicole Wilson

Class 2011
Education BA, Amherst College

Dr. Hal Dietz

Research Interests

Marfan Syndrome (MFS) is an autosomal dominant disorder caused by mutations in the fibrillin-1 gene. Symptoms manifest in the skeletal, ocular, and cardiovascular systems, and aortic dissection is the leading cause of death. Previous studies in our lab using mouse models of MFS have demonstrated that fibrillin-1 negatively regulates TGF-β in the extracellular matrix, and that symptoms in MFS mice can be partially or fully rescued by systemic TGF-β antagonism. Subsequent work has shown that increased activation of the noncanonical ERK pathway is a main driver of MFS aortic disease pathogenesis, but downstream mechanisms remain to be elucidated.

One of the major challenges that must be overcome when implicating molecular pathways in a severely diseased tissue is differentiating pathogenic events from those that are compensatory or irrelevant. Employing a MFS-specific conditional provocation could provide a useful filter for distinguishing between these types of events. It has been shown in our lab that calcium channel blocker (CCB) administration to MFS mice leads to a tripling of ascending aortic size within four weeks of starting treatment, and this exacerbation of the phenotype is accompanied by a further increase in ERK activation and can be rescued by treatment with an ERK inhibitor. It is my intention to utilize this gene-by-environment interaction as a filter for transcriptome profiling data to identify events that occur in tight temporal sequence with this conditional provocation. Successful identification of the disease-driving pathways will be informative for patient counseling and treatment of MFS and related disorders.