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Ocular degenerative and neovascular processes

Age Related Macular disease and Diabetic Retinopathy are the two most common diseases that lead to irreversible blindness.  Both are marked by neuronal and microvascular degeneration and subsequent neovascularization.  Understanding these pathological mechanisms is the way to new efficient therapies.

Age Related Macular Disease

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among older adults. The most prominent pathologic features of AMD involve lesions of the photoreceptors, retinal pigment epithelium (RPE), Bruchs membrane (BM) and the choriocapillaris. Early AMD is characterized by sub-RPE debris in BM (Drusen, white yellowish dots visible in funduscopy), changes in RPE pigmentation and by thinning and obliteration of the choriocapillary layer. Two clinical forms of late AMD are distinguished: - the ‘dry’ form characterized by geographic atrophy of RPE and choroid (geographic atrophy, GA) and the ‘wet’ form, which also includes choroidal neovascularization (CNV). Even though geographic atrophy is itself severely disabeling, it is the complications associated.

Microglia in AMD

Recently, we identified a dysfunction in an inflammatory factor (CX3CR1) in AMD patients that is involved in macrophage mobility.  We showed that the invalidation of this factor in animal models leads to resident macrophage (Microglial Cells) accumulation in the photoreceptor cell layer and subsequent neuronal degeneration and pathological neovascularization similar to that of AMD (Combadiere et al. JCI 2007).  This data supports the importance of Microglial Cells (MC) and immunologic mediators in the development of AMD. Collaborators: Christophe Combadière’s Laboratory, Pr Francine Behar-Cohen’s department of Ophthalmology at Hôtel Dieu and Salomon Yves Cohen’s Centre d’Angiographie et de Laser.

Microglia and Angiogenesis

Angiogenesis plays a major role in the wet form of AMD, where new  pathological vessels from under the retina. Several groups have observed microglia extending their processes to orientate towards and contact blood vessels as they form. However, the functional significance of this remained speculative. We illustrated that microglial deficiencies are associated with reduced developmental vascularization, a consequence which microglia reconstitution is able to restore. Moreover, we demonstrate that microglial loss is observed in two different models of retinopathy of prematurity (ROP), a result of free radical damage, which may explain in part the impaired vascularization that characterizes this disease. Our findings highlight a novel role of microglia, one that broadens its traditional definition as merely an immunocompetent cell and which may help to disclose novel therapeutics targeting retinal vascular pathologies (Checcin et al. IOVS 06). This work was a collaboration with Sylvain Chemtob’s Laboratory.

Future directions

Our goal is to decipher the mechanism that leads to the accumulation of MCs in the photoreceptor cell layer and isolate the microglial mediators responsible for degeneration and neovascularization.  Developing a therapy that effectively disrupts these mediators holds the promise of preventing and reversing this blindness causing condition. This project is supported by an ERC starting Grant (210345-Microglia and AMD)

The scavenger receptor CD36 and choroidal involution

Little is known about the molecular mechanisms that underlie dry AMD and, consequently, there is no cure for it. In this study, we tested whether a molecule called CD36, which is expressed on the surface of RPE cells, is involved in dry AMD. CD36 is a scavenger receptor—which means it binds many potentially harmful molecules including oxidized fats (which are present in the photoreceptor outer segments) and is involved in their phagocytosis. Phagocytosis itself induces the expression of several proteins in the RPE cells, including COX2, a “proangiogenic” protein that stimulates the growth of blood vessels. Putting this information together, the researchers hypothesized that a defect in CD36 might cause the characteristic retinal atrophy (by preventing the phagocytosis of worn-out photoreceptor outer segments) and choroidal involution (by preventing the induction of COX2 expression and consequently the maintenance of the blood vessels in the choroid) of dry AMD (Houssier et al. PLoS Medecine 08). This work was a collaboration with Sylvain Chemtobs and Huy Ongs Laboratories.

Group Leader

Florian Sennlaub
[more information]

Contact

Institut de la Vision

17, rue Moreau
75012 Paris
France

Email:
Florian.sennlaub[at]inserm.fr

Website:
http://www.crcjussieu.fr/

Methodology

  • Molecular Biology
  • Cell Culture
  • Animal Models

Current Research Projects

  • Project 1:
    Microglia and AMD
  • Project 2:
    CD36 and AMD

Scientific Cooperations

  • Cooperation 1:
    Christoph Comabière, Inserm U345, Paris
  • Cooperation 2:
    Sylvain Chemtob, Hopital Ste Justine, Montréal
  • Cooperation 3:
    Huy Ongs, Université de Montréal, Montréal
  • Cooperation 4:
    Francine Behar-Cohen, Hôtel Dieu, Paris

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