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Therapeutics against lung inflammation

Friday 11 December 2015

Therapeutics against lung inflammation
Interaction of collectin-derivatives with immune cells


Research Institute:
Division Molecular Host Defence, Department of Infectious Diseases, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CM Utrecht.

Background
Inflammation is an essential component of many lung diseases, including respiratory infections, asthma, COPD (Chronic Obstructive Pulmonary Disease), lung cancer, and granulomatous lung diseases. Excessive inflammatory responses may result in endothelial and alveolar damage, pulmonary edema, and reduced surfactant production/function, resulting in impairment of gas exchance. Ultimately, this may lead to progressive respiratory failure causing Acute Lung Injury (ALI) or the more severe Acute Respiratory Distress Syndrome (ARDS), an often fatal disease with high mortality rates.
Inhaled pathogens encounter various lines of defence before infection is established and two so-called ’lung collectins’, surfactant protein A (SP-A) and D (SP-D), are known to play important roles in protecting the lungs from infection by a broad range of inhaled microorganisms. Binding of SP-A and SP-D to these respiratory pathogens results in immediate inhibition of infection and simultaneously marks these pathogens for destruction by host immune cells (macrophages, neutrophils). In vivo studies have also demonstrated that collectins play crucial roles in modulating the inflammatory response by affecting immune cell activation and proliferation. Recent investigations have revealed that the inhibitory immune receptor "Leukocyte Associated Ig-like Receptor-1 (LAIR-1)" might be an important anti-inflammatory trigger of pulmonary immune cells that can be modulated by SP-D in the lung.

Aim
Develop recombinant SP-D variants to investigate the molecular interactions between SP-D and
LAIR and generate SP-D-based therapeutics with distinct anti-inflammatory properties.

Project approach and methodology
This study will be performed in collaboration with the Department of Immunology, University Medical Centre (WKZ), Utrecht, The Netherlands. Most experimental work will be carried out at the division of MHD at UU. The first stage of this project aims to design and express SP-D-based recombinant proteins and to develop isolation strategies to enable the production and molecular characterization of highly-purified preparations that are suitable for studies with immune cells. The second stage of this project is focused on dissecting the mechanism of interaction between the SP-D variants on one hand, and purified LAIR and/or LAIR-expressing cells on the other hand by using various functional cell-based assays. Ultimately, these studies may contribute to the development of novel anti-inflammatory agents that reduce excessive airway inflammatory responses and prevent progressive lung damage.

Contact
For additional inquiries, please contact:
Martin van Eijk, PhD.
T: 030 253 5361
M:06 537 35 985
E: m.vaneijk@uu.nl