Project description
Controlling migration across the body's internal borders to treat disease
The cells and tissues in the body act like little countries defending their borders, carefully controlling what goes in and out as an integral part of homeostasis and signalling. They can also coordinate activities. Among the allies in these functionally relevant synergies are blood and lymphatic vessels, critical for managing fluid flow. When the collaboration breaks down, it can lead to fluid build-up, chronic inflammation and even neurological and cardiovascular disease. BreakingBarriers is studying molecules that modulate the barriers in these two systems both in health and disease. Insight could provide novel ways to treat numerous diseases and conditions ranging from enhanced drug delivery to the brain to lowering lipid uptake to combat obesity.
Objective
Tissue homeostasis requires coordinated barrier function in blood and lymphatic vessels. Opening of junctions between endothelial cells (ECs) lining blood vessels leads to tissue fluid accumulation that is drained by lymphatic vessels. A pathological increase in blood vessel permeability or lack or malfunction of lymphatic vessels leads to edema and associated defects in macromolecule and immune cell clearance. Unbalanced barrier function between blood and lymphatic vessels contributes to neurodegeneration, chronic inflammation, and cardiovascular disease. In this proposal, we seek to gain mechanistic understanding into coordination of barrier function between blood and lymphatic vessels, how this process is altered in disease models and how it can be manipulated for therapeutic purposes. We will focus on two critical barriers with diametrically opposing functions, the blood-brain barrier (BBB) and the lymphatic capillary barrier (LCB). ECs of the BBB form very tight junctions that restrict paracellular access to the brain. In contrast, open junctions of the LCB ensure uptake of extravasated fluid, macromolecules and immune cells, as well as lipid in the gut. We have identified novel effectors of BBB and LCB junctions and will determine their role in adult homeostasis and in disease models. Mouse genetic gain and loss of function approaches in combination with histological, ultrastructural, functional and molecular analysis will determine mechanisms underlying formation of tissue specific EC barriers. Deliverables include in vivo validated targets that could be used for i) opening the BBB on demand for drug delivery into the brain, and ii) to lower plasma lipid uptake via interfering with the LCB, with implications for prevention of obesity, cardiovascular disease and inflammation. These pioneering studies promise to open up new opportunities for research and treatment of neurovascular and cardiovascular disease.
Fields of science
Not validated
Not validated
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- medical and health sciencesbasic medicinephysiologyhomeostasis
- medical and health scienceshealth sciencesnutritionobesity
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
75654 Paris
France