Studies of diseases associated with receptors of the TGF-ß superfamily

Our research concentrates on vascular diseases caused by mutations in genes coding for receptors of the transforming growth factor beta (TGF-ß) superfamily. We focus primarily on endoglin and ALK1, which are specifically expressed on endothelial cells. These cells line the blood vessels and are essential for providing oxygen and nutrients to all tissues as well as serving a barrier function and sensing changes in blood flow and pressure. Mutations in endoglin and ALK1 genes are responsible for Hereditary Hemorrhagic Telangiectasia (HHT) and in some cases pulmonary arterial hypertension. Our recent studies have demonstrated that a soluble form of endoglin is associated with preeclampsia,
a pregnancy disorder characterized by increased blood pressure in the mother. We have shown that TGF-ß can cause vasorelaxation and stimulate endothelial nitric oxide synthase (eNOS) activity. Furthermore endoglin interacts with eNOS and in fact the TGF-ß receptor complex associates with the eNOS activation complex, to regulate blood vasomotor function. To delineate TGF-ß signaling pathways mediated by endothelial specific receptors, we have performed robotic screens of proteinprotein interactions in transfected mammalian cells. We have identified several novel interacting partners of endoglin and ALK1 receptors.

Our current aim is to determine how these novel interacting proteins interact with the receptors, mediate signaling and engage in cross-talk with known pathways. We have generated mouse models of HHT and pulmonary arterial hypertension, which are useful in determine the protein interactions and pathways affected in these diseases. Since TGF-ß is a critical contributor to several cancers, we are studying the possible role of some of the novel receptor interacting proteins in ovarian cancer. Our primary focus is on molecular changes associated with early events in the disease. We are comparing ovarian epithelial cells derived from women with BRCA mutations to those of normal women in an attempt to delineate early changes caused by these mutations and potentially contributing to cell transformation. Our work may lead to the identification of early markers needed for the early diagnostic of this devastating cancer.

Graduate Students:

Selected References:

• Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M and Letarte, M. (2005) A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ. Res. 96: 684-92.

• Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M and Karumanchi SA. (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 12: 642-649.

• Abdalla SA and Letarte M. (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43: 97-110.

• Motamed-Khorasani A, Jurisica I, Letarte M, Shaw PA, Parkes RK, Zhang X, Evangelou, A, Rosen B, Murphy KJ and Brown TJ. (2007) Differentially androgen-modulated genes in ovarian epithelial cells from BRCA mutation carriers and control patients predict ovarian cancer survival and disease progression. Oncogene 26:198-214.