Blodkärlsbiologi i hälsa och sjukdom
Tidsperiod: 2016-01-01 till 2019-12-31
Projektledare: Lena Claesson-Welsh
Budget: 6 000 000 SEK
The ability of blood vessels to dynamically regulate their permeability to solute, molecules and cells is critical in physiological processes such as wound healing and it is vital for tissue homeostasis. On the other hand, acute permeability in response e.g. to trauma may cause tissue damage. Also, chronic vascular permeability such as in tumors and chronic inflammatory conditions results in persistent edema and increased interstitial pressure, which exacerbates diseases and hampers treatment. Permeability to larger molecules and inflammatory cells involves the transient formation of gaps between endothelial cells, induced by growth factors such as vascular endothelial growth factor (VEGF). The proposed research will provide knowledge on the dynamic regulation of vascular permeability, a spatiotemporally tightly regulated process involving communication between a range of molecules and cells. We will exploit novel mouse models, high resolution imaging and tools for in vivo analyses of signal transduction, to show how vascular junctions open and close in wild type and disease-challenged mice. We will study the effect on lymphatics and the contribution of flow, vasotone and blood pressure. Through the holistic approach, we will learn not only how vascular integrity and leak are controlled in vivo, but also about the metabolic consequences for the afflicted tissue and how the barrier and tissue homoestasis may be restored. We will exploit our findings to develop drugs that have the potential to impact the clinical outcome of a range of pathological processes propagated by lack of vascular integrity, not only by suppressing disease progression but also to make conventional therapy more efficient, allowing lower doses and reduced side effects. Such drugs therefore herald an entirely new therapeutic approach for common diseases such as cancer, retinopathy and myocardial infarction, which would serve important individual and societal needs.