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The effect of CFTR on islet development and signalling

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  • Full or part time
    Prof N McClenaghan
    Dr C Kelly
  • Application Deadline
    Applications accepted all year round

About This PhD Project

Project Description

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene.

Abnormal CFTR leads to dehydrated, acidic secretions, which drive CF-pathogenesis. Although CF mortality results primarily from lung disease, CF-related diabetes (CFRD) is the largest co-morbidity, significantly accelerating lung decline. The exact cause(s) of CFRD remains unclear,1 particularly the role of CFTR in normal functioning of endocrine pancreas. It is widely accepted that CFTR mutations reduce bicarbonate-rich secretions from pancreatic ducts leading to fibrotic progression and loss of exocrine/endocrine pancreatic tissue. However, primary research confirms an intrinsic role for CFTR in the regulation of insulin secretion from pancreatic islets.2-4 Given the detrimental impact of CFRD on lung function and life expectancy in CF patients, better understanding of these processes is urgently needed.

Aim: Determine the role of CFTR, and the effect of CFTR mutation, in islet cell development and signalling
Rationale: Islet architecture is critical to normal function, and disruption of islets hampers biphasic insulin secretion. Abnormalities in islet morphology have been reported in newborn CF ferrets3 and in autopsy reports on children who died with CF. GJ proteins, including connexin 36, 43 (endocrine pancreas), connexin 45 (exocrine pancreas) and the ubiquitous E-Cadherin, interact with CFTR.6 Reciprocal signalling has been demonstrated with CFTR regulating connexin mediated cell-cell communication. Our working hypothesis proposes that mutant CFTR alters islet structure and related islet cell signalling leading to
disturbances in insulin homeostasis.

The three primary objectives to be undertaken during the PhD are briefly as follows:
1 Study of islet formation in the absence of functional CFTR
2 Examination of effect of mutant CFTR on islet-cell interactions
3 Study downstream effects of mutant CFTR on cell-cell communication pathways

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