The endothelium is the central mediator of cystic fibrosis associated liver disease.

Employer
KU Leuven
Location
Europe
Posted
October 11 2017
Position Type
Full Time
Organization Type
Academia

For the department of Development & Regeneration (Organ systems) we are searching a talented enthusiastic PhD student for a project entitled "The endothelium is the central mediator of cystic fibrosis associated liver disease." The host laboratory of Prof. Peter Carmeliet, Laboratory of Angiogenesis and Vascular Metabolism, is highly renowned in the fields of angiogenesis and metabolism.


The lab is part of the VIB and KU Leuven and structurally organized into several core facilities, focusing on selected topics, and managed by senior technicians with a high-degree of specialized expertise. These technical core-facilities provide the necessary suppo... For more information see https://icts.kuleuven.be/apps/jobsite/vacatures/54413663

Cystic fibrosis (CF) is the most frequent life-shortening genetic disorder in the Caucasian population, with an incidence of 1 to 2,500-4,000. After pulmonary disease, CF-associated liver disease (CFLD) is the second non-transplant related cause of mortality (3.5-7.8% in historical cohorts). Based on insensitive clinical, biochemical and radiological parameters, the prevalence of liver disease is estimated at 26 to 45% and thus highly relevant to be further studied.


In the past CFLD was suggested to have a biliary mechanism. However, we have recently shown that there is in fact a vascular mechanism. It presents as non-cirrhotic portal hypertension (NCPH) indicated by a presinusoidal portal hypertension (hepatic portal venous pressure gradient measurements), and histology with an obliterative portal branch venopathy, sinusoidal dilatation, and nodular regenerative hyperplasia in the absence of cirrhosis.


There is increasing evidence of endothelial involvement in CF pathology and endothelial cells (ECs), the cells lining blood vessels, are central in the pathogenesis of NCPH. Therefore, we hypothesize an important contribution of the ECs in CFLD that presents as NCPH.


To this extent, we will first study liver biopsies from 4 liver centers with CF patients with a special interest on the vascular changes and the role of the endothelium (immunohistochemistry and electron microscopy). In a next phase, to gain further insight into the mechanism involved, we will we will focus on ECs themselves by studying CFTR genetically-silenced HUVECs (human umbilical vein ECs), isolated ECs from the liver of murine CFTR KO model, and CF and CFLD patient-derived BOECs (blood outgrowth ECs). We will combine untargeted analysis (metabolomics and transcriptomics), targeted functional (proliferation, migration, angiogenesis, activation, NO production) and metabolic assays (tracing experiments, energy production, redox homeostasis), as endothelial function is determined by EC metabolism. This will elucidate the EC characteristics as a player in CF pathology. Moreover, by the use of BOECs from CF and CFLD patients, we will elucidate crucial steps in the development of CFLD.


Understanding of the pathophysiology of CFLD could assist in defining this disease and provide new targets for treatment as there is currently no preventive or therapeutic option.



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