THE IMPORTANCE OF MACROPHAGE SENESCENCE IN REGULATING ANGIOGENESIS IN THE EYE

描述(申请人提供)：巨噬细胞是天然免疫手臂的关键组成部分，在调节对肿瘤、感染和炎症的初始免疫反应中起关键作用。巨噬细胞在维持眼睛的免疫豁免权方面也是一个核心角色。免疫衰老的特征是免疫系统的先天和适应性两个部分的年龄相关变化。先天性免疫，特别是巨噬细胞的功能，在眼睛中受到特别的关注，因为它可以调节发育和发育后的血管生成。眼部新生血管在老年性黄斑变性、糖尿病视网膜病变、早产儿视网膜病变和眼内肿瘤等多种眼部疾病的视力损害和失明中起核心作用。这项建议中描述的工作将有助于阐明衰老导致巨噬细胞向有害的促血管生成表型的功能漂移的机制。我们的研究还将测试改变巨噬细胞极化如何决定眼睛中血管生成的命运。这些问题与巨噬细胞在AMD中的重要性尤其相关。这些目标将通过以下方式实现：a)量化IL-10激活的巨噬细胞中与年龄相关的导致抗血管生成功能丧失的信号通路的变化，以及b)证明斑疹蛋白的主要成分胆固醇的异常处理导致老年巨噬细胞成为促血管生成细胞。

DESCRIPTION (provided by applicant): The macrophage is a key component of the innate arm of immunity and is critical in regulating initial immune response to tumors, infections and in inflammation. The macrophage is also a central player in sustaining immune privilege in the eye. Immunosenescence is characterized by age-related changes in both the innate and adaptive compartments of the immune system. Innate immunity, specifically macrophage function, has received particular attention in the eye as it can modulate developmental and post-developmental angiogenesis. Ocular neovascularization plays a central role in visual impairment and blindness in several disease states of the eye, including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and intraocular tumors. The work described in this proposal will help elucidate the mechanisms by which senescence induces a functional drift in macrophages towards a deleterious pro-angiogenic phenotype. Our studies will also test how altering macrophage polarization determines angiogenic fate in the eye. These questions are especially relevant to the importance of macrophages in AMD. These goals will be accomplished by: a) Quantifying age-related changes in IL-10 activated signaling pathways in macrophages that lead to loss of anti-angiogenic function and b) Demonstrating that abnormal processing of cholesterol, a dominant component of drusen, causes old macrophages to become pro- angiogenic.