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应答中至关重要。巨噬细胞也是维持眼睛免疫特权的核心参与者。免疫衰老的特征在于免疫系统的先天和适应性区室中与年龄相关的变化。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。眼部新生血管形成在眼部的几种疾病状态中的视力损害和失明中起核心作用，所述疾病状态包括年龄相关性黄斑变性、糖尿病性视网膜病变、早产儿视网膜病变和眼内肿瘤。这项工作中描述的建议将有助于阐明衰老诱导巨噬细胞功能漂移的机制，朝着有害的促血管生成表型。我们的研究还将测试如何改变巨噬细胞极化决定血管生成的命运在眼睛。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活化信号传导途径中导致抗血管生成功能丧失的年龄相关变化，和B）证明胆固醇（玻璃疣的主要成分）的异常加工导致老年巨噬细胞变得促血管生成。公共卫生相关性：血管增生性眼病占所有年龄段失明负担的绝大部分。如本提案中所确定的，与异常血管生成的病理生理学相关的导致免疫功能障碍的机制将帮助我们设计基于免疫的疗法，以改善疾病进展并最终失明。 公共卫生相关性：免疫细胞和免疫细胞分泌的细胞因子，特别是巨噬细胞，正在成为调节与异常血管生长相关的眼部疾病的核心参与者。这些包括年龄相关性黄斑变性、早产儿视网膜病变和糖尿病视网膜病变。我们的目标是了解巨噬细胞功能障碍促进疾病进展的机制，并希望提供新的见解，以设计未来的治疗方法来预防这些疾病导致的失明。

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.