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Chronic bleeding due to epistaxis and gastrointestinal bleeding telangiectasia in HHT leads to transfusion dependence, iron infusion dependence,
decreased quality of life and premature death.
Novel therapies such as pomolidamide, Avastin and pazopanib may be new promising therapies to lead to remission in bleeding and reduce the burden of disease
BMP9 circulates in the blood and signals through the endothelial cell. IN the absence of Alk 1, such as in HHT, the vessels become over-active. The overactivity can be partially balanced by activation of a second signaling pathway: notch. Would targeting notch be a useful drug target to reverse AVM formation
Natural genetic variation between individuals can influence the outcome of carrying an HHT mutation. Some gene variants may be protective while others may increase the risk of AVM or telangiectasis. By identifying the variant genes that alter risk of AVM may give clues to the molecular mechanisms of AVM formation and provide new drug targets
Alk 1 or Endoglin deficient endothelial cells promote recruitment of monocytes/macrophages and differentiation of them can play a critical role in development of arteriovenous malformations. Will targeting macrophage recruitment or activation instead of angiogenesis result in greater understanding leading to new therapeutic targets to control disease?
Endothelial cells derive from cells in the bone marrow. Circulating precursor endothelial cells contribute to newly forming vessels.
Do Alk 1 and/or Endogln mutations affect the functions of these cells once they incorporate into growing vessels. These vessels then go on to form arteriovenous malformations
Liver arteriovenous venous malformations creates a high flow shunt that over time creates high output cardiac failure with no effective treatments.
Why loss of endoglin causes HHT is not known. Endoglin is expressed by vascular smooth muscle cells and endothelial cells.
What is the role of endogin on vascular smooth muscle cells and why its loss contributes to HHT and other vascular malformations
How do gene mutations in endoglin and alk 1 create arteriovenous malformations leading to disease. Alk 1 and endoglin are receptors in TGFB/BMP family signaling. TGFB/BMP have roles in vascular development, remodeling and maintenance in vascular integrity. Understanding the downstream effect will lead to advancements in reducing genetic diseases such as HHT as well as vascular malformations in general