Project Details
Description
PROJECT SUMMARY
Subretinal fibrosis, an end-stage fibrous scar of neovascular age-related macular degeneration (nAMD),
compromises highly organized anatomical layers and tightly coordinated cellular interactions, inevitably leading
to irreversible visual impairment. The current treatment for subretinal fibrosis is limited and therefore, new
therapeutic strategies for the inhibition of subretinal fibrosis are imperative.
Multiple cell types, including endothelial cells (ECs), retinal pigment epithelium (RPE) cells, macrophages
and glial cells, contribute to subretinal fibrosis by either differentiating into mesenchymal-like cells and further
differentiating into α-smooth muscle actin-positive myofibroblasts and/or producing profibrotic and
proinflammatory factors. However, the underlying mechanisms for these cellular and molecular activities remain
poorly defined. Adenosine receptor 2A (Adora2a) has been implicated in various vascular diseases and
inflammation. Our preliminary data here show that (i) the level of Adora2a expression was increased in subretinal
lesions of laser-induced CNV in mice; (ii) the size of subretinal fibrosis was markedly decreased in lesions of
laser–induced CNV in Adora2a-deficient mice; (iii) endothelial-to-mesenchymal transition (EndMT) occurred to
choroidal ECs (CECs) and EndMT participated in the formation of subretinal fibrosis in laser-induced mouse
CNV; (iv) Tgfb2-induced EndMT was decreased for Adora2a-deficient CECs; (v) macrophage-to-myofibroblast
transition (MMT) in laser-induced subretinal fibrotic lesions was markedly reduced in Adora2a-deficient mice; (vi)
Adora2a-deficient bone marrow derived macrophages (BMDMs) had a compromised production of profibrotic
factors after stimulation with Tgfb2; and (vii) the levels of hypoxia-inducible factor (Hif) 1a or 2a dynamically
correlated with those of Adora2a in the above pathological alterations. Thus, we hypothesize that Adora2a-
mediated Hif signaling in CECs and infiltrated macrophages enhance fibrotic effects leading to increased
formation of fibrotic lesions in CNV. To test our hypothesis, we have generated mice with inducible global
Adora2a deficiency in Vldlr-/- mice, endothelial lineage tracing mice, inducible endothelial Adora2a deficiency in
C57BL/6j mice, and myeloid Adora2a deficiency in C57BL/6j mice. We established an ex vivo approach to culture
mouse CECs and in vitro approaches to generate BMDMs. We will investigate the effect of Adora2a inactivation
in CECs and myeloid cells in subretinal fibrosis using specific genetic and pharmacological tools and assess
subretinal fibrosis using an integrated approach of in vivo, ex vivo, and in vitro models. Our study will define the
role of Adora2a in the development of subretinal fibrosis and provide the basis for using ADORA2A inhibition as
a novel approach in the prevention and treatment of blinding retinal disease.
Status | Not started |
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Funding
- National Eye Institute: $437,751.00
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