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About Sickkids
About SickKids

Michelle Letarte, PhD

Research Institute
Senior Scientist Emeritus
Molecular Medicine

University of Toronto
Professor
Immunology, Medical Biophysics, Obstetrics/Gynecology and Paediatrics


Phone: 416-813-6258
Fax: 416-813-7877
Email: michelle.letarte@sickkids.ca

Brief Biography

  • PhD in Biochemistry from the University of Ottawa and post-doctoral training in Molecular Immunology from the University of Oxford.
  • Professor in the Department of Immunology, with cross-appointments to Medical Biophysics, Paediatrics, and Obstetrics/Gynecology.
  • Highly involved in Hereditary Hemorrhagic Telangiectasia (HHT) basic and translational research. Member of the International Medical and Scientific Advisory Board.

Research Interests

  • Role of Endoglin and ALK1 in endothelial cells and in Hereditary Hemorrhagic Telangiectasia (HHT) and Pulmonary Arterial Hypertension (PAH)
  • Regulation of blood vessel function by transforming growth factor-beta (TGF-ß) and bone morphogenetic proteins (BMP)
  • Pathological angiogenesis
  • Protein networks of endoglin and ALK1
  • Soluble endoglin and preeclampsia

Research Activities

Our main objectives are to understand the function of endoglin and to characterize the endothelial cell pathways altered in Hereditary hemorrhagic telangiectasia (HHT). We discovered endoglin, the gene coding for a glycoprotein of 180 kDa expressed at high levels on the endothelium of all blood vessels. We also showed that endoglin is a co-receptor for TGF-ß and the gene mutated in HHT type 1 (HHT1).

HHT is an autosomal dominant vascular disorder present in 1 in 8,000 people and associated with frequent nosebleeds and arteriovenous malformations that can lead to stroke and internal hemorrhages. We study the underlying mechanisms of this genetic disorder. Gene haploinsufficiency and a 50% reduction in functional endoglin protein in blood vessels are responsible for HHT. We made an animal model of disease, the endoglin heterozygous (Eng+/-) mouse, that allows us to perform experiments with isolated vessels and cells. We also test the in vivo effects of factors such as inflammation contributing to disease, and of potential new treatments.

One of our main aims is to elucidate how reduced expression of endoglin can lead to dilated vessels and arteriovenous malformations. We demonstrated that endoglin associates with and stabilizes endothelial nitric oxide synthase (eNOS), the enzyme regulating the production of NO, the major endothelium-dependent vasodilator. In fact, in HHT1, eNOS activation is impaired leading to superoxide, which likely initiates focal vascular damage. We are therefore testing in Eng+/- mice the effects of anti-oxidants, which prevented abnormal dilatation of isolated mouse vessels.

Our laboratory established a research diagnostic test for HHT and reported 155 mutations for HHT1 and HHT2. A clinical mutation diagnostic test is now available in several countries and having a strong impact on detection of patients at risk.

In a recent collaborative study, we have shown that a soluble circulating form of endoglin is associated with preeclampsia, a common complication of pregnancy where the mother develops systemic hypertension. A recombinant form of soluble endoglin is able to suppress the vasodilatory effects of TGF-ß and induce preeclampsia in mice. A commercial diagnostic test is under development that should predict preeclampsia several weeks prior to its clinical onset and facilitate management of pregnancy.

Future Research Interests

Our current and future studies focus on understanding the protein networks of Endoglin, ALK1 and the BMP type II receptor (BMPR2; mutated in familial PAH) and the mechanistic relationships between HHT and PAH, supported by emerging clinical and animal model studies. ALK1 is the gene mutated in HHT2 and in some inherited cases of Pulmonary Arterial Hypertension (PAH). We are currently working with the pulmonary system of both Eng+/- and Alk1+/- mice, where we observe signs of PAH. We use mouse imaging, hemodynamic and biochemical measurements to define the changes in the vasculature and in angiogenesis.

Molecular studies are aimed at defining the crosstalk and co-regulation of TGF-ß/BMP pathways implicating endoglin, ALK1 and BMPR2. Using high throughput screens, we have identified multiple new partners for endoglin and ALK1. We propose to map in normal endothelial cells the downstream pathways linked to the receptors via these novel partners and examine their regulation by TGF-ß and BMP-9. We will determine which of these novel partners and downstream pathways are affected in mice and human with HHT and PAH. These studies should identify new pathways relevant to vascular integrity and novel targets for disease prevention or treatment.

We are also pursuing the endoglin/eNOS axis with the aim of defining the pathways contributing to the generation of superoxide in these vascular diseases. We are testing anti-oxidants in Eng+/- and Alk1+/- mice in an attempt to prevent the onset of HHT and PAH manifestations.

We are also comparing the extent of inflammatory bowel disease in Eng+/- and control mice. Our preliminary data show that the Eng+/- mice develop more severe colitis, implying pathological angiogenesis in the progression of this disease. Novel partners of endoglin identified in the high throughput screen and likely implicated in mediating this inflammatory and angiogenic bowel disease will be tested. The goal is to identify novel targets regulated by TGF-ß/BMP and their receptors, that could improve the outcome of this disease.

External Funding

  • Canadian Institutes of Health Research (CIHR)
  • Heart and Stroke Foundation of Canada
  • HHT International Foundation

Publications

Thomas B, Eyries M, Montagne K, Martin S, Agrapart M, Simerman-François R, Letarte M, Soubrier F. Altered endothelial gene expression associated with hereditary haemorrhagic telangiectasia (HHT). Eur. J. Clin. Invest. 37:580-588, 2007.

Motamed-Khorasani A, Jurisica I, Letarte M, Shaw PA, Parkes RK, Zhang X, Evangelou A, Rosen B, Murphy KJ, Brown TJ. 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, 2007.

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

Jerkic M, Rodríguez-Barbero A, Prieto M, Toporsian M, Pericacho M, Rivas-Elena JV, Obreo J, Wang A, Pérez-Barriocanal F, Arévalo M, Bernabéu C, Letarte M, López-Novoa JM. Reduced angiogenic responses in adult endoglin heterozygous mice. Cardiovasc. Res. 69:845-854, 2006.

Abdalla S, Letarte, M. Hereditary hemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J. Med. Genet. 43:97-110, 2006.

Pece-Barbara N, Vera S, Kathirkamathamby K, Liebner S, Di Guglielmo GM, Dejana E, Wrana JL, Letarte M. Endoglin null endothelial cells proliferate faster, and are more responsive to TGF-ß1 with higher affinity receptors and an activated ALK1 pathway. J. Biol. Chem. 280:27800-27808, 2005.

Letarte M, Voulgaraki D, Hartherley D, Foster-Cuevas M, Saunders NJ, Barclay N. Analysis of leukocyte membrane protein interactions using protein microarrays. BMC Biochem. 6:2 doi:10.1186/1471-2091-6-2, 2005.

Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M, Letarte M. A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ. Res. 96:684-692, 2005.

Abdalla SA, Gallione CJ, Barst RJ, Horn EM, Knowles JA, Marchuk DA, Letarte M, Morse JH. Primary pulmonary hypertension in families with hereditary hemorrhagic telangiectasia. Eur. Respir. J. 23:373-377, 2004.

Abdalla S, Cymerman U, Johnson R, Deber C, Letarte M. Disease-associated mutations in conserved residues of the ALK-1 kinase domain. Eur. J. Hum. Genet. 11:279-287, 2003.

Satomi J, Mount RJ, Paterson A, Toporsian M, Wallace C, Harriso, RV, Letarte M. Cerebral vascular abnormatlities in a murine model of hereditary hemorrhagic telangiectasia. Stroke, 34:783-789 2003.

Bourdeau A, Faughnan ME, McDonald ML, Paterson A, Wanless IR, Letarte M. Potential role of modifier genes influencing TGF-ß1 levels in the development of vascular defects in endoglin heterozygous mice with Hereditary Hemorrhagic Telangiectasia. Am. J. Pathol. 158:2011-2020, 2001.

Matsubara S, Bourdeau A, terBrugge KG, Wallace C, Letarte M. Analysis of endoglin expression in normal brain tissue and in cerebral arteriovenous malformations. Stroke, 31:2653-2660, 2000.

Abdalla SA, Pece-Barbara N, Vera S, Tapia E, Paez E, Bernabeu C, Letarte M. Analysis of ALK-1 and endoglin in newborns from families with Hereditary Hemorrhagic Telangiectasia Type 2. Hum. Mol. Genet., 9:1227-1237, 2000.

Bourdeau A, Cymerman U, Paquet ME, Meschino W, McKinnon WC, Guttmacher AE, Becker L, Letarte M. Endoglin expression is reduced on normal vessels but still detectable in arteriovenous malformations of patients with Hereditary Hemorrhagic Telangiectasia type 1. Am. J. Pathol. 156:911-923, 2000.

Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. Journal of Biological Chemistry, 274: 584-594, 1999.

Caniggia I, Taylor CV, Ritchie JWK, Lye SJ, Letarte M. Engoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants. Endocrinology, 138: 4977-4988, 1997.

Pece N, Vera S, Cymerman U, White RI Jr., Wrana JL, Letarte M. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. Journal of Clinical Investigation, 100: 2568-2579, 1997.