CCR3: a molecular marker for neovascular AMD

描述（由申请人提供）：老年性黄斑变性（AMD）影响的美国人与所有癌症的总和一样多，是阿尔茨海默病的两倍。AMD严重视力丧失的主要原因是脉络膜新生血管（CNV），即异常血管生长到视网膜中。尽管使用最近批准的靶向血管内皮生长因子（VEGF）-A的分子治疗剂，但大多数患者没有恢复良好的功能性视力，并且显著部分进展为法律的盲。这是由于目前无法在CNV侵入视网膜并导致结构和功能组织损伤之前检测到CNV。在新的和令人兴奋的发现中，我们报告了对人CNV具有特异性的第一个分子标记物的发现（Takeda等人，Nature 2009）：CCR 3，一种以促进嗜酸性粒细胞和肥大细胞运输而闻名的趋化因子受体，仅在由于AMD引起的CNV的情况下在体内人脉络膜内皮细胞中表达。靶向CCR 3或其eotaxin配体在体外和体内抑制血管生成，并且比VEGF-A阻断剂更上级和更安全。使用靶向CCR 3的功能化量子点的非侵入性体内生物成像检测到小鼠脉络膜内的CNV，该CNV尚未侵入视网膜并且对于荧光素血管造影是不可见的。这些发现将CCR 3定义为人类CNV的新的特异性分子早期诊断和治疗靶点。在这个提议中，我们将定义CCR 3/嗜酸性粒细胞趋化因子轴和衰老，补体激活和氧化应激之间的生物学关系，以破译这些已建立的AMD发病因素如何调节疾病的新生血管进展。我们还将创建和优化新的荧光光学生物成像CCR 3靶向探针，可以检测脉络膜内，“亚临床”CNV。这些研究正是对这一挑战主题的回应，因为它们将阐明免疫系统如何调节AMD中血管生成开关的这种特定特征，并创新性地利用它，通过将早期检测与靶向治疗相结合来预防视力丧失。因此，该提案完全符合NEI视网膜疾病战略计划的5年计划目标。它还推进了《美国复苏和再投资法案》的目标，因为如果得到资助，它将为三个人创造或保留就业机会，并为第三方供应商和供应商提供经济利益。我们承诺在2010年10月的最后期限前完成该项目，并愿意完成NIH概述的与该项目有关的季度报告。 公共卫生相关性：脉络膜新生血管形成（CNV）造成90%的由年龄相关性黄斑变性（AMD）引起的严重视力丧失，这是美国老年人失明的主要原因。我们最近发现CCR 3是第一个与人CNV特异性表达的分子，我们令人兴奋的新发现是CCR 3靶向分子成像探针可以在视网膜浸润前检测CNV，这支持了AMD中CCR 3生物学的研究和生物成像方式的优化。该提案可以通过引入创新的生物成像策略来改变临床实践范例，该策略能够早期检测CNV以用于可以预防视力丧失的靶向治疗。它还将通过创造或保留多个就业机会来推进ARRA的目标，并为肯塔基州医学院以及第三方供应商和供应商提供经济利益，该大学一直作为经济发展的主要力量为肯塔基州联邦服务。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) affects as many Americans as all cancers combined and twice as many as Alzheimer's disease. The overwhelming cause of severe vision loss in AMD is choroidal neovascularization (CNV), the growth of abnormal blood vessels into the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial growth factor (VEGF)-A, the majority of patients do not recover good, functional vision, and a significant fraction progress to legal blindness. This is due to the present inability to detect CNV before it invades the retina and causes structural and functional tissue damage. In new and exciting findings, we are reporting the discovery of the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009): CCR3, a chemokine receptor best known for promoting eosinophil and mast cell trafficking, is expressed in human choroidal endothelial cells in vivo only in the setting of CNV due to AMD. Targeting CCR3 or its eotaxin ligands inhibited angiogenesis in vitro and in vivo, and was both superior to and safer than VEGF-A blockade. Non-invasive in vivo bioimaging using functionalized quantum dots targeting CCR3 detected CNV within the mouse choroid that had not yet invaded the retina and was invisible to fluorescein angiography. These findings define CCR3 as a novel specific molecular early diagnostic and therapeutic target in human CNV. In this proposal, we will define the biological relationships between the CCR3/eotaxin axis and aging, complement activation, and oxidative stress to decipher how these established AMD pathogenetic factors regulate the neovascular progression of disease. We will also create and optimize new fluorescent optical bioimaging CCR3-targeting probes that can detect intrachoroidal, "subclinical" CNV. These studies respond precisely to this Challenge Topic as they will illuminate how the immune system regulates this specific signature of the angiogenic switch in AMD, and innovatively exploit it to enable prevention of vision loss by coupling early detection with targeted therapy. As such, this proposal is perfectly aligned with the 5-year program goals of the NEI's Retinal Diseases strategic plan. It also advances the goals of the American Recovery and Reinvestment Act as it will, if funded, create or retain jobs for three individuals, and provide economic benefits to third- party suppliers and vendors. We are committed to complete the program by the determined October 2010 deadline, and are willing to complete quarterly reports pertaining to this project as outlined by NIH. PUBLIC HEALTH RELEVANCE: Choroidal neovascularization (CNV) is responsible for 90% of severe vision loss due to age- related macular degeneration (AMD), the leading cause of blindness among the elderly in the United States. Our recent discovery of CCR3 as the first molecule specifically expressed with human CNV and our exciting new finding that CCR3-targeting molecular imaging probes can detect CNV before retinal invasion support the investigation of CCR3 biology in AMD and optimization of bioimaging modalities. This proposal can transform the clinical practice paradigm by introducing an innovative bioimaging strategy that enables early detection of CNV for targeted therapy that can prevent vision loss. It also will advance the goals of the ARRA by creating or retaining multiple jobs and provide economic benefit to the University of Kentucky College of Medicine, which has consistently served the Commonwealth of Kentucky as a principal force for economic development, and third-party suppliers and vendors.