Harry C. Dietz
Johns Hopkins University
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Primary Section: 42, Medical Physiology and Metabolism Secondary Section: 41, Medical Genetics, Hematology, and Oncology Membership Type:
Member
(elected 2011)
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Research Interests
As a cardiologist and human geneticist, my work has focused on molecular determinants of arterial wall homeostasis, with a particular emphasis on the pathogenesis and treatment of aortic aneurysm. Using genetically-defined mouse models of Marfan syndrome, we found that disease manifestations in many tissues, including the aorta, associated with increased activation of and signaling by the multi-potential cytokine transforming growth factor-beta (TGF-beta) and that postnatal aneurysm progression and tear could be prevented by TGF-beta antagonists including angiotensin II type 1 (AT1) receptor blockers (ARBs), a class of medication that is now in clinical trial for Marfan syndrome. More recently, we showed that noncanonical TGF-beta signaling (and specifically ERK activation) drives aneurysm progression in Marfan syndrome and that this mechanism is relevant to other inherited presentations of aortic aneurysm. We recognized and characterized a novel aneurysm syndrome (Loeys-Dietz syndrome) that is caused by primary mutations in the genes encoding either subunit of the TGF-beta receptor that associate with paradoxically increased TGF-beta signaling in the aorta. We are using mouse models of this condition to elucidate how altered signaling gives rise to component phenotypes that are common in the general population including aortic aneurysm, skeletal muscle myopathy, cleft palate, clubfoot deformity and TH2-mediated allergic disease.
