Descripción del proyecto
Un modelo tridimensional de la barrera hematoencefálica para estudiar la patología de la malaria cerebral
La malaria es un importante problema de salud pública que causa más de cuatrocientas mil muertes al año. La malaria cerebral (MC) se caracteriza por la retención de los eritrocitos infectados en la microvasculatura del encéfalo, la alteración de la barrera hematoencefálica (BHE, o BBB por sus siglas en inglés) y edema cerebral, lo que causa una mortalidad elevada. El proyecto financiado con fondos europeos Mal3D-BBB pretende modelar la patología de la MC humana con métodos de bioingeniería «in vitro» revolucionarios. Los investigadores desarrollarán modelos de BHE con redes microfluídicas tridimensionales (3D) que incorporen múltiples tipos celulares: células endoteliales de la microvasculatura del encéfalo, astrocitos y pericitos. La plataforma desarrollada pretende recrear los índices de permeabilidad de la BHE fisiológica y se usará para comprender los mecanismos moleculares de la alteración de la BHE tras la infección por «Plasmodium Falciparum», y si los factores del parásito y el hospedador se combinan para aumentar la patología.
Objetivo
Malaria is a major public health problem and it still causes more than 400,000 deaths per year. Cerebral malaria (CM) is one of the most serious complications, with 20% mortality rates even after administration of fast-acting antimalarials. CM pathology is characterized by sequestration of P. falciparum-infected red blood cells (iRBC) in the brain microvasculature, blood-brain barrier (BBB) disruption, and brain swelling.
Our current knowledge of CM is primarly based on autopsy studies, because of the absence of suitable animal models. However, there are numerous pathogenic aspects that cannot be studied from post-mortem samples, such as disease progression. In Mal3D-BBB, we bypass these limitations by recreating the human CM pathology with cutting-edge in vitro bioengineering approaches. Rather than using 2D endothelial monolayers, we will develop BBB models with 3D tubular geometry that incorporate multiple cell types: brain microvascular endothelial cells, astrocytes and pericytes. We will mimic vessel dimensions and flow dynamics of the brain vasculature with the goal to recreate physiological BBB permeability rates. Using such technology brings a unique angle to malaria research to evaluate in a controlled and systematic way 1) the molecular mechanisms of BBB disruption after P. falciparum sequestration, and 2) whether parasite and host factors synergize to increase pathology. The findings obtained by this cutting-edge technology will be further validated in samples from CM patients, whose neurovascular pathology has been thoroughly characterized using MRI.
Our interdisciplinary approach aims to provide a holistic understanding of CM malaria pathogenesis. In return, this knowledge will identify new pathways that could be counteracted to develop therapies to reduce patient mortality. In a broader context, we will build an innovative platform that captures the complex physiology of the BBB, and can be translated to the study of other neurovascular diseases.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
69117 Heidelberg
Alemania