Hal Dietz, MD

Leveraging Nature’s Success: Lessons from Modifiers of Marfan Syndrome and Related Aneurysm Conditions

Dysregulation of TGFβ signaling has been implicated in many disease states including Marfan syndrome (MFS), a condition caused by deficiency of the extracellular matrix protein fibrillin-1. Many manifestations of MFS can be attenuated in mouse models using interventions that antagonize TGFβ signaling. TGFβ can initiate both canonical (Smad-dependent) and noncanonical (prominently including the MAPKs ERK, JNK and p38) signaling cascades. Multiple lines of evidence will be presented that implicate ERK signaling as the primary TGFβ-dependent event that drives disease including the ability of ERK antagonists to achieve phenotypic rescue. Despite this progress, our understanding of how fibrillin-1 deficiency initiates altered TGFβ activity remains incomplete, as does knowledge regarding events that culminate in tissue failure or that that account for the wide intrafamilial variability in the severity of vascular disease. This talk will highlight work focusing on the use of conditional provocations in model systems to develop and test both pathogenic hypotheses and novel therapeutic strategies. Specific insights regarding the cause and treatment of pregnancy-associated aortic dissection and deleterious iatrogenic gene-by-environment interactions will be discussed. An additional emphasis is the use of genetic methods to determine how nature modifies MFS, both in humans and mice. In such unbiased discovery studies, the identification of modifier loci, genes and alleles capable of protecting from the cardiovascular consequences of MFS in predisposed individuals has reinforced numerous pathogenic principles that derived from decades of hypothesis-dependent research and has identified multiple additional therapeutic targets that have already been validated in preclinical studies.

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Affiliation: Victor A. McKusick Professor of Medicine and Genetics Investigator, Howard Hughes Medical Institute Director, William S. Smilow Center for Marfan Syndrome Research Institute of Genetic Medicine Departments of Pediatrics, Medicine, and Molecular Biology & Genetics Johns Hopkins University School of Medicine, Baltimore, MD