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Project Summary

Myeloid cells have been implicated in the development of choroidal neovascularisation (CNV) in age-related macular degeneration (AMD) which is one of the leading causes of blindness worldwide. Resident microglial cells (MG) constitute the major myeloid cell population in the retina and subretinal space. They are complimented by recruited myeloid cells (MC) from the blood during disease and inflammation when the blood-brain barrier is breached. The cell biology underlying the change from health to disease and the distinct functions of resident MG and recruited MC in CNV development remain ill defined. The ultimate goal of this study is to explore the role of MG and MC in three cardinal aspects of CNV pathology: (i) the age-dependent expansion of MG and MC to the subretinal space, (ii) the recruitment of MG and MC to sites of CNV and (iii) the relative contribution of MG and MC cells to the development of CNV. To achieve these goals we will study the temporal and spatial distribution of MG and MC in the retina and subretinal space in health and in two mouse models of CNV by in vivo imaging, immunohistochemistry, flow cytometry and fate mapping. Next, we will investigate the expression profile of isolated quiescent and activated MG and MC using RNA sequencing. Functionally, we will explore the specific roles of three key factors involved in myeloid cell activation, maturation and M1/M2 polarization, namely the hypoxia-inducible transcription factor 1a (HIF1a), the Interferon-regulating factor 8 (IRF8) and the Interferon-regulating factor 5 (IRF5). Finally, we will examine the potential of pharmaceutical inhibition of MG and MC activation and recruitment for treating CNV. Together, these studies may lay the foundation for the development of innovative, therapeutic approaches in neovascular AMD that are directed against pathologic MG/MC activation without compromising homeostatic functions.