THE IMPORTANCE OF MACROPHAGE SENESCENCE IN REGULATING ANGIOGENESIS IN THE EYE

描述（由申请人提供）：巨噬细胞是先天免疫臂的关键组成部分，在调节对肿瘤、感染和炎症的初始免疫反应中起关键作用。巨噬细胞也是维持眼睛免疫特权的核心角色。免疫衰老的特征是免疫系统先天和适应性区室的年龄相关变化。先天免疫，特别是巨噬细胞功能，在眼睛中受到特别关注，因为它可以调节发育和发育后的血管生成。眼部新生血管在几种眼部疾病（包括年龄相关性黄斑变性、糖尿病视网膜病变、早产儿视网膜病变和眼内肿瘤）的视力损害和失明中起着核心作用。本提案中描述的工作将有助于阐明衰老诱导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血管生成的命运。这些问题与巨噬细胞在AMD中的重要性特别相关。这些目标将通过以下方式实现：a)量化巨噬细胞中IL-10激活信号通路的年龄相关变化，导致抗血管生成功能丧失；b)证明胆固醇（drusen的主要成分）的异常加工导致老年巨噬细胞成为促血管生成细胞。公共卫生相关性：血管增生性眼病占所有年龄组失明负担的绝大部分。导致免疫功能障碍的机制，如本提案中所确定的，与异常血管生成的病理生理学相关，将帮助我们设计出基于免疫的治疗方法，改善疾病进展，最终失明。

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. Public Health Relevance: Angioproliferative eye diseases account for a significant majority of blindness burden across all age groups. Mechanisms that lead to immune dysfunction as identified in this proposal that are relevant to the pathophysiology of abnormal angiogenesis will help us devise immune based therapies that ameliorate disease progression and ultimately blindness. PUBLIC HEALTH RELEVANCE: Immune cells and cytokines secreted by immune cells, specifically macrophages, are emerging as central players in regulating eye diseases associated with abnormal blood vessel growth. These include age-related macular degeneration, retinopathy of prematurity, and diabetic retinopathy. We aim to understand the mechanisms by which macrophage dysfunction promotes disease progression and hope to provide new insights in order to design future therapies to prevent blindness from these diseases.