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Inflammation in retinal degeneration and vascular remodeling

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Team leaders : Florian Sennlaub & Michel Paques

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Introduction

Our team studies the characterization of cellular and molecular mechanisms of age-related macular disease and ischemic proliferative retinopathies with particular interest in inflammatory mechanisms that lead to neuronal degeneration and vascular remodeling 

Presentation

Age Related Macular disease (AMD) and ischemic retinopathies (IR), such as retinal vein occlusion, diabetic retinopathy and retinopathy of prematurity, are the two most common cause of blindness. Both are marked by chronic neuro-inflammation, and neuronal and microvascular degeneration and remodelling, which can be complicated by neovascularization. We have focused our interest on the role of chronic inflammation in the pathogenesis of these diseases. We have shown that (i) inflammatory Mφ and MCs accumulate in affected areas of the retina; (iii) certain transgenic mice develop age dependent primary retinal MC/Mφ accumulation; (iii) this accumulation is associated with retinal degeneration and altered vascular remodeling. We showed that inflammatory MC/Mφ recruitment and accumulation to the retina are an important aggravating factor for irreversible neurodegeneration and vascular remodeling as observed in AMD and IR.


Research areas

 

  • AMD and inflammation (Florian Sennlaub) : Recent evidence suggests an implication of inflammatory mediators in AMD. We have focused our interest on the role of microglial cells (MC) and Macrophages (Mf) in this condition. Our data indicates that (i) MC/Mf accumulate in affected areas of the macula in human AMD ; (ii) MC/Mf accumulate leads to/contributes to Drusen formation, retinal degeneration and exacerbated neovascularization, similarly to AMD. Our data suggests an important role of subretinal MC accumulation in the development of AMD. Inhibiting subretinal inflammation in AMD is a promising avenue to develop new efficient therapies.

  • Hyperglycemia, retinopathy of prematurity (ROP) and diabetic retinopathy (DR) (Xavier Guillonneau): Diabetic microangiopathy affects the majority of vascular beds in the body, leading to tissue ischemia. In the retina the microangiopathy leads to an ischemic phase which is followed by pathological neovascularization and neuronal degeneration. We have developed a model of Neonatal Hyperglycemia induced Retinopathy (NHiR) that leads to severe retinal inflammation and alterations of physiological angiogenesis. Our data shows that neonatal hyperglycemia in rodents induces an ischemic retinopathy with vascular development arrest and neuronal degeneration very similar to diabetic retinopathy. We analyze the molecular mechanisms that lead to hyperglycemia-induced MC accumulation and activation, as well as the mediators of vascular and neuronal degeneration.

  • Retinal vein occlusion (RVO) (Michel Paques) : RVO affects an estimated 1 million people worldwide. We have established a mouse model of RVO that closely mimicks the human disease. Furthermore, we have developped an imaging technique that allows the direct visualization of the retinal vessel walls in vivo in humans and animals. We aim to (i) identify genes involved in the human disease in hereditary RVO (ii) analyse vessel wall flexibility in familial RVO and hypertension and its influence on veinous blood flow in vivo (iii) analyse the expression and function of the identified genes in vessel structure and in RVO animal models. The aim of this project is to identify molecular pathways that lead to blood flow disturbance and RVO in the retina. A better understanding of RVO pathomechanism will allow us to identify future drug targets.

 

Ressources

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