The retina is composed of the neural retina and the retinal pigment epithelium (RPE). The RPE phagocytes photoreceptor outer segments, supports survival of photoreceptors, regenerates the phototransduction component and participates in the choroidal blood-retina barrier. Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss, affecting one million persons in France. The RPE is the prime target of the disease. RPE cell damage/dysfunction induces degeneration of the photoreceptors, leading to a loss of central vision. Early stage of AMD is characterized by the formation of drusen that are deposits of extracellular material located underneath the RPE. Drusen provokes a inflammatory response and are associated with RPE atrophy. Photoreceptors overlying drusen died by apoptosis, whereas Müller glial cells are activated. Proliferation and migration of vascular endothelial cells (CEC) through the RPE, results in blood-retina barrier disruption. Treatments target the blinding complications of AMD, rather than its causes and often therapeutic intervention fails to prevent blindness. There is no totally satisfactory animal model of AMD, a situation which impairs research efforts. AMD disease mechanisms are poorly understood. Interaction between inflammation and oxidative stress may be one of the mechanism involved in AMD and have important implications for the development of new treatments. - The presence of Amyloid beta (Ab) in drusen is consistent with the hypothesis of oxidative/inflammatory stress-mediated AMD, although the role of APP (amyloid protein precursor) and the effects of Ab in the retina remains unknown. We hypothesized that Ab may participate in retinal degeneration through RPE damage/dysfunction, apoptosis of photoreceptors, microglial activation, Müller glial cell activation, retina detachment from RPE and finally choroidal neovascularization. - - The aim of this study is to analyze the transcriptional regulation patterns, regulatory mechanisms and pathogenic pathways during Ab-induced retina degeneration by using inter-disciplinary and complementary methods to obtain an integrated view of the different Ab effects and of the interactions between the different pathogenic pathways involved in this process. We will use both cell cultures and animal models, including primate with a macula and AD mouse models (Partner 1), determine the cellular and molecular mechanisms involved in these processes, using quantitative methods, including macroarrays and will propose targeted therapeutic strategies in regard to the specific functions of the retinal and choroidal cells by collaborating with a toxicology laboratory (Partner 2).Functional tests will determine the impact of Ab-induced retina degeneration and treatments on the visual functions. - Hypothesis 1: Ab induces damage/dysfunction in RPE cells. Specific aim: to determine 1- the effects of Ab on the specific function of the RPE, 2- the role of the macula and 3- the molecular mechanisms involved in this process. - Hypothesis 2: Ab alters photoreceptors homeostasis. Specific aim: 1- to determine if Ab-induced photoreceptor apoptosis is directly due to Ab or mediated through RPE, because photoreceptors survival is dependent on RPE and 2- to characterize the molecular pathways involved in this process. - Hypothesis 3: Effects of Ab is mediated through microglial activation. Specific aim: to determine if microglia activation plays a protective role against Ab through degradation of Ab, or in the contrary if microglia will amplify the Ab-mediated oxidative stress, leading to enhanced degeneration. - Hypothesis 4: Ab induces Müller glial cell activation and choroidal neovascularization. Specific aim: to determine if 1- Ab-mediated retinal Müller glial activation participate in the loop of Ab production, leading to enhanced retina degeneration and 2- if Ab is able to induce neovascularization after the disruption of the choroidal blood-retina barrier. - ...
Monsieur Frédéric MASCARELLI (INSERM ADR PARIS VI SAINT ANTOINE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Inserm Paris 6 INSERM ADR PARIS VI SAINT ANTOINE
CNRS DELEGATION REGIONALE ILE DE FRANCE EST
UNIVERSITE RENE DESCARTES PARIS 5
Help of the ANR 457,600 euros
Beginning and duration of the scientific project: - 48 Months