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Department of Cellular and Molecular Medicine

doetschman portraitLaboratory of Tom Doetschman

The function of the 3 TGFβ ligands and of FGF2 and its high and low molecular weight isoforms are being determined using genetically engineered mice. The research has resulted in mouse models for the following human diseases: i) congenital heart defects, ii) cardiac hypertrophy, iii) autoimmune disease, and iv) colon cancer. These mouse models have provided a better understanding of the roles that TGFβs and FGF2s play in the development and/or prevention of these diseases. We are presently pursuing the following research projects.

Connective Tissue Diseases

Rienhoff Syndrome: Rienhoff Syndrome is a connective tissue disorder that features skeletal muscle hypotonia, arachnodactyly and arthrogryposis. It is unknown whether other features of connective tissue disorders such as aortic aneurysm/dissection will appear with age. We have made a Rienhoff Syndrome mouse strain carrying the same TGFβ3 mutation as the patient in order to investigate the cellular and molecular mechanisms underlying these connective tissue features.

Congenital Heart Disease: Cardiac valve thickening and aortic dilation and rupture are major cardiovascular phenotypes of both syndromic and non-syndromic connective tissue diseases in human and are manifested by matrix structural disorders that lead to functional deficiencies. The valve disorder is modeled in TGFβ2-deficient mice and is thought to be caused by persistent EMT and poor differentiation and remodeling of the subsequent cushion mesenchyme into properly structured valves. Combined deficiencies of TGFβ2 & TGFβ3 lead to aortic dilation and wall thickening. These TGFβs are now being used to improve seeding of smooth muscle cells in synthetic vessels.

Other Research Area

Colon Cancer: Loss of TGFβ signaling is associated with approximately 30% of all human colon cancer. TGFβ1-deficient mice model human colon cancer. This model has revealed tumor suppressor roles of TGFβ1 in the areas of regulating oxidative stress and inflammatory response, maintenance of colon epithelial tissue integrity and regulation of gut bacterial flora.

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