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）：与年龄相关的黄斑变性（AMD）影响着所有癌症合并的美国人，是阿尔茨海默氏病的两倍。 AMD严重视力丧失的压倒性原因是脉络膜新生血管形成（CNV），这是血管异常的血管生长到视网膜中。尽管使用了最近批准的靶向血管内皮生长因子（VEGF）的分子疗法-A，但大多数患者却没有恢复良好，功能性视力，并且对法律失明的分数很大。这是由于目前无法在CNV侵入视网膜之前检测到CNV并造成结构和功能性组织损伤。在新的令人兴奋的发现中，我们报告了针对人CNV的第一个分子标记的发现（Takeda等，自然，2009年）：CCR3是一种趋化因子受体，以促进嗜酸性粒细胞和桅杆细胞运输而闻名，在人类脉络膜内皮细胞中表现在vivo中，仅在CNV的情况下以Amd的含量为单位。靶向CCR3或其eotaxin配体在体外和体内抑制血管生成，并且比VEGF-A阻滞优于和更安全。使用靶向CCR3的功能化量子点，在尚未侵入视网膜的小鼠脉络膜内检测到的CCR3的量子点非侵入性生物成像，并且对荧光素血管造影是看不见的。这些发现将CCR3定义为人类CNV中一种新型的特异性分子诊断和治疗靶标。在此提案中，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，以解读这些确定的AMD致病因素如何调节疾病的新生血管进展。我们还将创建并优化可以检测肺内“亚临床” CNV的新的荧光光学生物成像CCR3靶向探针。这些研究对这个挑战主题做出了准确的反应，因为它们将阐明免疫系统如何调节AMD中血管生成转换的特定特定签名，并创新地利用它来通过与目标疗法耦合早期检测来预防视力丧失。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。它还可以促进《美国恢复和再投资法》的目标，如果资助的话，为三个人创造或保留工作，并为第三方供应商和供应商提供经济利益。我们致力于完成2010年10月截止日期，并愿意完成与NIH概述的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％由于年龄相关的黄斑变性而导致的严重视力丧失（AMD），这是美国老年人失明的主要原因。我们最近将CCR3作为第一个分子的发现，该分子是通过人CNV专门表达的，我们令人兴奋的新发现，即涉及CCR3的分子成像探针可以在视网膜侵袭支持AMD中的CCR3生物学和生物成像模态的优化之前检测CNV。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，该策略能够尽早发现CNV用于靶向疗法，以防止视力丧失。它还将通过创造或留住多个工作，并为肯塔基大学医学院提供经济利益来促进ARRA的目标，肯塔基大学医学院一直为肯塔基州的联邦作为经济发展的主要力量，第三方供应商和供应商。