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The Role of Type III Transforming Growth Factor-β Receptor in Regulating ALK1 Signaling and Endothelial Biology

dc.contributor.advisor Blobe, Gerard C Hector-Greene, Melissa Erica 2018-05-31T21:11:51Z 2020-04-26T08:17:08Z 2017
dc.description.abstract <p>The Transforming Growth Factor-β (TGF-β) superfamily of ligands and receptors play critical roles in angiogenesis, evidenced by their essential role in physiologic angiogenesis and their perturbation in pathologic angiogenesis. In development, loss or mutation of Activin receptor-Like Kinase 1 (ALK1), an endothelium- specific TGF-β superfamily receptor kinase, leads to disordered angiogenesis and results in the hereditary vascular disease, Hereditary Hemorrhagic Telangiectasia (HHT). A co-receptor in the TGF-β superfamily, the type III Transforming Growth Factor-β Receptor (TβRIII), is known to be important for the vasculature, with genetic deletion of TβRIII resulting in embryonic lethality in mice characterized by severe defects in cardiac and hepatic vasculogenesis. Despite these observations, how TβRIII regulates the vasculature remains unknown. The aim of this study is to elucidate how TβRIII regulates ALK1 signaling and endothelial behavior. </p><p>Here, we establish that vascular endothelial cells express relatively high levels of TβRIII, alongside the canonical endothelium-restricted co-receptor, endoglin. Moreover, using biophysical and biochemical techniques, we have established that TβRIII forms stable complexes with ALK1. Through genetic knockout approaches using CRISPR, we demonstrate that loss of TβRIII impairs ALK1-induced Smad phosphorylation as well as endothelial angiogenic potential, including the ability to form capillary tubes.</p><p>We have uncovered a novel TβRIII/ALK1 interaction, the role of TβRIII in ALK1-mediated signaling and TβRIII’s role in functional endothelial biology. Understanding TβRIII’s function in the developing endothelium may lead to the development of innovative pharmacological treatments aimed at normalizing angiogenesis and improve our ability to anticipate the potential adverse effects of therapies targeting TGF-β superfamily receptors.</p>
dc.subject Cellular biology
dc.subject Molecular biology
dc.subject Biology
dc.subject ALK1
dc.subject Angiogenesis
dc.subject Betaglycan
dc.subject Endoglin
dc.subject Endothelial biology
dc.title The Role of Type III Transforming Growth Factor-β Receptor in Regulating ALK1 Signaling and Endothelial Biology
dc.type Dissertation
dc.department Molecular Cancer Biology
duke.embargo.months 23

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