Completed Cells, Biochemistry & Physiology Cancer

The role of two key intracellular trafficking genes, VPS33B and VIPAR in development and disease.

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £1.3M
Period Sept 2011 — Aug 2017

In plain English

AI plain-English summary

Children born with ARC syndrome cannot absorb nutrients from food, form proper bile in the liver, or develop normal kidneys and brains. The disease is caused by mutations in two genes, VPS33B and VIPAR, which together control how cells sort and deliver proteins to the right places. Without this sorting system, epithelial cells—the cells that line organs like the liver, kidney, and gut—fail to establish the correct "top-bottom" polarity needed for them to function. This project aims to map the exact protein-trafficking pathway that VPS33B and VIPAR control, identify which key proteins depend on this pathway for their correct location, and understand how defective trafficking disrupts the junctions that hold epithelial cells together. The researcher will use proteomics to find interacting proteins, test their roles in zebrafish development, and study the effects of gene knockout in mice. This is fundamental science. There is no immediate treatment for ARC syndrome. But by defining the molecular machinery behind a devastating developmental disorder, the work could eventually reveal targets for drugs that bypass or correct the trafficking defect. Similar fundamental studies of intracellular transport have already led to therapies for other rare genetic diseases.

View original technical description
ARC is a rare multisystem disorder. My group has identified 2 genes (VPS33B and VIPAR) in which mutations cause ARC. VPS33B and VIPAR are involved in trafficking pathway linked to regulation of apical basolateral polarity. Establishment of apical basolateral polarity affects the development and function of epithelial organs such as liver, kidney and CNS. Aim: To define the role of VIPAR/VPS33B in intracellular protein trafficking and cell differentiation. Goals: 1. Delineate the VIPAR/VPS33 B apical membrane trafficking pathway 2. Identify apical membrane proteins, whose correct localisation is dependent on VIPAR/VPS33B pathway. 3. Define the signalling pathways that link VIPAR/VPS33B complex and apical junction complex formation. 4. Develop methods to test potential therapeutic molecules that may correct the cell phenotype in VPS33B and VIPAR deficiencies Design and Methodology: I will use proteomics technology to screen for the putative VPS33B/VIPAR interacting proteins, whic h will then be tested in zebrafish for involvement in development. Knockdown polarised cell lines will be used to study the trafficking pathway dependant on VPS33B/VIPAR and the signalling mechanisms linking defective trafficking with apical junction protein expression. The importance of Vps33b and Vipar in development and function of mammalian organs will be studied in mouse knockout models.

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Researchers

Paul Gissen (EPMC Awardee)

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Original classification

Senior Research Fellowship Clinical

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