CCR3: a molecular marker for neovascular AMD

CCR3：新生血管性 AMD 的分子标志物

• 批准号: 7935227
• 负责人: Jayakrishna Ambati
• 金额: $ 50万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935227
• 关键词: Accounting; Affect; Affinity; Age; Age related macular degeneration; Aging; Alzheimer' s Disease; American; Angiogenic Switch; Animal Model; Antibodies; Automobile Driving; Biodistribution; Biological; Biological Markers; Biology; Blindness; Blood Vessels; Bruch' s basal membrane structure; Cells; Choroid; Choroidal Neovascularization; Commit; Complement Activation; Coupled; Coupling; Diagnostic; Disease; Disease Progression; Dyes; Early Diagnosis; Economic Development; Economics; Elderly; Endothelial Cells; Eotaxin; Epidemic; Exudative age-related macular degeneration; Eye; FDA approved; Fab Immunoglobulins; Fluorescein Angiography; Funding; Future; Genetic; Goals; Grant; Growth; Human; Immune; Immune system; In Vitro; Individual; Intervention; Invaded; Investigation; Kentucky; Legal Blindness; Ligands; Malignant Neoplasms; Maps; Medicine; Modality; Molecular; Molecular Profiling; Molecular Target; Mus; Natural Immunity; Nature; Nonexudative age-related macular degeneration; Occupations; Optics; Outcome; Oxidative Stress; Panthera leo; Pathogenesis; Pathology; Patients; Pharmacotherapy; Photoreceptors; Plasma Proteins; Prevalence; Prevention; Quantum Dots; Recovery; Relative (related person); Reporting; Retina; Retinal; Retinal Diseases; Source; Specificity; Specimen; Staging; Strategic Planning; Structure of retinal pigment epithelium; Techniques; Testing; Tissues; United States; United States National Institutes of Health; Universities; Vascular Endothelial Growth Factor A; Vendor; Vision; Visual; aging population; allergic response; angiogenesis; bioimaging; chemokine receptor; clinical practice; college; cost; cytokine; eosinophil; imaging probe; improved; in vivo; innovation; legally blind; mast cell; molecular imaging; molecular marker; mouse model; nanocrystal; neovascular; novel; prevent; programs; public health relevance; therapeutic target; trafficking

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.

描述（由申请人提供）：年龄相关性黄斑变性 (AMD) 影响的美国人数量相当于所有癌症的总和，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。尽管使用了最近批准的针对血管内皮生长因子 (VEGF)-A 的分子疗法，但大多数患者并未恢复良好的功能性视力，并且很大一部分患者进展为法定失明。这是由于目前无法在 CNV 侵入视网膜并造成结构和功能组织损伤之前检测到它。在令人兴奋的新发现中，我们报告了第一个针对人类 CNV 的分子标记的发现（Takeda 等人 Nature 2009）：CCR3 是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 AMD 导致的 CNV 情况下在体内的人脉络膜内皮细胞中表达。靶向 CCR3 或其嗜酸细胞活化趋化因子配体可在体外和体内抑制血管生成，并且优于 VEGF-A 阻断剂，并且比 VEGF-A 阻断剂更安全。使用靶向 CCR3 的功能化量子点进行非侵入性体内生物成像，检测到小鼠脉络膜内尚未侵入视网膜且荧光素血管造影不可见的 CNV。这些发现将 CCR3 定义为人类 CNV 的新型特异性分子早期诊断和治疗靶点。在本提案中，我们将定义 CCR3/eotaxin 轴与衰老、补体激活和氧化应激之间的生物学关系，以破译这些已确定的 AMD 致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型荧光光学生物成像 CCR3 靶向探针，可检测脉络膜内的“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，并创新地利用它通过早期检测与靶向治疗相结合来预防视力丧失。因此，该提案与 NEI 视网膜疾病战略计划的 5 年计划目标完全一致。它还推进了《美国复苏和再投资法案》的目标，因为如果获得资助，它将为三个人创造或保留就业机会，并为第三方供应商和销售商提供经济利益。我们致力于在确定的 2010 年 10 月截止日期之前完成该计划，并愿意按照 NIH 的概述完成与该项目相关的季度报告。 公共健康相关性：脉络膜新生血管 (CNV) 导致 90% 的年龄相关性黄斑变性 (AMD) 导致的严重视力丧失，这是美国老年人失明的主要原因。我们最近发现 CCR3 作为第一个与人类 CNV 特异性表达的分子，以及我们令人兴奋的新发现，即 CCR3 靶向分子成像探针可以在视网膜侵袭之前检测 CNV，支持了 AMD 中 CCR3 生物学的研究和生物成像模式的优化。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式，该策略能够早期检测 CNV，以进行可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，并为肯塔基大学医学院以及第三方供应商和供应商提供经济效益，该医学院一直是肯塔基州经济发展的主要力量。