Targeting endothelial barriers to combat disease

Descripción del proyecto

Control de la migración a través de las fronteras interiores del cuerpo para tratar enfermedades

Las células y tejidos del cuerpo actúan como pequeños países que defienden sus fronteras controlando cuidadosamente lo que entra y sale como parte integrante de la homeostasis y la señalización. Además, pueden coordinar actividades. Entre los aliados de estas sinergias funcionalmente pertinentes figuran la sangre y los vasos linfáticos, que son fundamentales para gestionar el flujo de fluidos. La rotura de esta colaboración puede dar lugar a acumulación de líquidos, inflamación crónica e incluso enfermedades neurológicas y cardiovasculares. BreakingBarriers está estudiando las moléculas que modulan las barreras de estos dos sistemas en la salud y la enfermedad. La información podría aportar nuevas maneras de tratar numerosas enfermedades y afecciones que van desde la mejora de la administración de fármacos al encéfalo hasta la reducción de la absorción de líquidos con el fin de combatir la obesidad.

Objetivo

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.