The function of the 3 TGFb 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 are providing a better understanding of the roles that TGFbs and FGF2s play in the development and/or prevention of these diseases.
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 TGFb2-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. Aortic dilation and wall thickening occur in TGFb2/TGFb3 doubly deficient mice and are thought to result from dysfunction of the two developmentally derived sources of smooth muscle. dysfunction.
Cardiac Hypertrophy & Heart Failure
Multiple signaling pathways are involved in cardiac hypertrophy which if left untreated leads to heart failure. We have found that cardiac hypertrophy is strongly attenuated in FGF2-deficient mice and that the requirement for FGF2 in cardiac hypertrophy involves signaling through the ERK Map Kinase pathway. FGF2 has translationally derived isoforms, the differential functions of which are not known. Mice with subtle mutations in the translational start sites are under investigation to determine the specific functions and signaling pathways of the FGF2 protein isoforms in cardiac hypertrophy.
Other Research Areas
Autoimmune Disease: TGFb1 is known to play essential roles in immune regulation. TGFb1-deficient mice develop a multifocal autoimmune disease due hyperactive T cells. Analysis of these mice has revealed a novel TGFb1 signaling pathway that involves regulation of intracellular free calcium levels.
Colon Cancer: Loss of TGFb signaling is associated with approximately 30% of all human colon cancer. TGFb1-deficient mice model human colon cancer. This model has revealed tumor suppressor roles of TGFb1 in the areas of regulating oxidative stress and inflammatory response, maintenance of colon epithelial tissue integrity and regulation of gut bacterial flora.