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Systemic Inflammation in Cystic Fibrosis

Project Description

Cystic fibrosis (CF) is a heritable multisystem disease, involving the lungs, exocrine and endocrine glands, the intestines, and other organ systems. Tissue and organ inflammation are central contributors to disease expression and organ damage in CF. The exact mechanisms triggering pulmonary as well as systemic inflammation, however, remain unclear. Since a subset of CF patients develop arthritis and/or vasculitis, uncontrolled activation of systemic immune responses are likely to be involved in the pathophysiology of CF and its complications and sequelae. CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that encodes for a chloride and bicarbonate channel. Reduced or absent function of CFTR results in defective ion transport, and subsequently thickened mucus and altered salt-concentrations.
Cystic fibrosis affects more than 10,000 patients in the U.K., and despite early diagnosis and significant medical efforts, only about 50% of affected individuals reach their 40th birthday. Although new exciting treatments are available for a minority of CF patients with specific gene mutations, treatment for most currently involves supportive measures, treatment of complications such as diabetes, and antibiotic treatment of infections. Treatment of inflammatory complications (pulmonary inflammation, arthritis, vasculitis, etc.) is not standardized and is somewhat insufficient, and prognosis is poor.
Absent or reduced CFTR function contributes to altered sodium chloride concentrations in the airways. Not physiological salt concentrations and subsequently altered osmolality may be of central pathophysiological impact, since airway epithelia and immune cells closely interact and may therefore influence systemic immune responses. Indeed, increased dietary salt intake has been linked to pathological inflammatory conditions.
Bronchial epithelia and innate immune cells (neutrophilic granulocytes and monocytes) express so-called inflammasomes, multi-protein complexes that assemble in response to "danger signals". Inflammasomes are responsible for the activation of inflammatory caspases that mediate the activation and release of pro-inflammatory cytokines IL-1β and IL-18. Indeed, in a mouse model, NRLP3 inflammasomes have been demonstrated to act as sensors of extracellular osmolality that are triggered by increasing concentrations of extracellular sodium chloride. Thus, altered salt concentrations may trigger inflammatory responses and immune cell priming in the broncho-alveolar system and result in systemic inflammation in CF.
Provided they are not physiological, bronchial sodium chloride concentrations and osmolality together with the presence of severe pulmonary and systemic inflammatory complications in CF, targeting molecular mechanisms of inflammasome activation in cells and tissues of the broncho-alveolar system is a promising candidate in the search for therapeutic targets for individualized, target-directed, and tolerable treatments. Indeed, untargeted inflammasome inhibition improved the outcome in CF. Continuous systemic treatment with the non-steroidal anti-inflammatory drug (NSAID) ibuprofen reduces the progression of the lung disease. NSAIDs have recently been reported to reduce NLRP3 inflammasome activity. Since target-directed and more potent inflammasome inhibitors will be available and cytokine blocking strategies are already standard-of-care in other inflammatory conditions, the proposed project promises direct implications on future treatment options and outcomes in CF.
In this project, we will follow four main objectives to investigate the potential involvement of aberrant salt concentrations and/or altered osmo-tolerance in organ and systemic inflammation in CF:
Objective 1: Enhanced expression and activation of NLRP3 inflammasomes through sodium chloride in epithelial and innate immune cells.
Objective 2: To test the hypothesis and validate findings from objective 1 in primary human epithelial and innate immune cells from patients with CF and controls.
Objective 3: Epigenetic dysregulation of inflammasome-associated genes as a result of increased salt exposure.
Objective 4: Alteration of inflammasome activation through available therapeutic agents.
Training and Support:
• The Ph.D. student will be based in state-of-the-art laboratory facilities in the ‘Institute in the Park’ that guarantee access to a wide range of equipment, allowing for the execution of outlined experiments. The proximity to Alder Hey Children’s Hospital is particularly beneficial given support from the NIHR Alder Hey Clinical Research Facility (Director: Beresford) including trained staff collecting bio-samples.
• The student will also be supported by the EATC4Children’s PDRAs on a day-to-day basis
To apply please send:
• Curriculum Vitae
• Letter of intention, explaining interest and why they think they are well placed to do this

Please email direct enquiries to Laura Whitty.

Funding Notes

• Home/EU Tuition Fees. (Note rate for 2019/20 is £4,327 which will increase accordingly)
• Stipend at Research Council UK (RCUK) Rate. (Note rate for 2019/20 is £15,009 which will increase accordingly).
The above funding is in place for 3 years (Institute + Research Funded)
Funding also includes match-funding for lab’ consumables – 3 years at £5k per year.
The position is funded through UoL ITM (Ethel Boyce Fellowship) and the Alder Hey Children’s NHS Foundation Trust (matched funding).


• The student will be co-supervised by Professors Christian M. Hedrich and Paul McNamara, two CIs with extensive experience with patient-focused immunological studies. The research groups of the CIs are experienced in necessary laboratory techniques, and will offer full support. Results and potential pitfalls will be discussed in weekly group meetings. Journal clubs and seminars are scheduled on a regular basis, and the Ph.D. student will be involved in both.

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