CCR3: a molecular marker for neovascular AMD

CCR3：新生血管性 AMD 的分子标志物

• 批准号: 7834091
• 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 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7834091
• 关键词: Accounting; Affect; Affinity; Age; Age related macular degeneration; Aging; Allergic; 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; 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; response; 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(申请人提供)：老年性黄斑变性(AMD)影响的美国人相当于所有癌症的总和，是阿尔茨海默病的两倍。导致AMD严重视力丧失的主要原因是脉络膜新生血管(CNV)，即异常血管进入视网膜的生长。尽管最近批准使用针对血管内皮生长因子(VEGF)-A的分子疗法，但大多数患者无法恢复良好的功能性视力，并且有相当一部分患者进展到合法失明。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它。在新的和令人兴奋的发现中，我们报告了第一个人类CNV特异性分子标记的发现(Takeda等人。《自然》2009)：CCR3是一种趋化因子受体，以促进嗜酸性粒细胞和肥大细胞的运输而闻名，仅在AMD所致的CNV环境中在活体人脉络膜内皮细胞中表达。靶向CCR3或其嗜酸性粒细胞趋化因子配体在体内外均可抑制血管生成，且优于血管内皮生长因子-A受体阻断剂，且比阻断血管内皮生长因子-A更安全。使用针对CCR3的功能化量子点的体内非侵入性生物成像在小鼠脉络膜中检测到尚未侵入视网膜且荧光素血管造影看不到的CNV。这些发现将CCR3定义为人类CNV的一个新的特异性分子早期诊断和治疗靶点。在这个提案中，我们将定义CCR3/eoaxin轴与衰老、补体激活和氧化应激之间的生物学关系，以破译这些已建立的AMD致病因子如何调节疾病的新血管进展。我们还将创造和优化新的荧光光学生物成像CCR3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一特定特征，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，这项建议与NEI的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，因为如果获得资金，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。我们承诺在确定的2010年10月的最后期限前完成该计划，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(CNV)是美国老年人失明的主要原因，老年性黄斑变性(AMD)导致的严重视力损失有90%是由CNV造成的。我们最近发现的CCR3是第一个与人CNV特异表达的分子，我们令人兴奋的新发现是，CCR3靶向的分子成像探针可以在视网膜侵袭之前检测到CNV，这为AMD的CCR3生物学研究和生物成像方式的优化提供了支持。这一建议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，以便进行靶向治疗，从而防止视力丧失。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利益。肯塔基大学医学院一直是肯塔基州联邦经济发展的主要力量。