Endothelial Cell Dysregulation in Neovascular AMD

新生血管性 AMD 中的内皮细胞失调

• 批准号: 8316114
• 负责人: Mark E Kleinman
• 金额: $ 32.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316114
• 关键词: Ablation; Accounting; Advisory Committees; Affect; Age related macular degeneration; Aging; American; Animal Model; Architecture; Area; Automobile Driving; Award; Basic Science; Biological; Biological Markers; Biology; Biomedical Research; Blindness; Blood; Blood Vessels; Bone Marrow Transplantation; Cell Line; Cells; Chairperson; Choroidal Neovascularization; Chromatin Remodeling Factor; Clinical; Clinical Research; Complement Activation; Coupled; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Drusen; Dyes; Early Diagnosis; Early treatment; Endothelial Cells; Engineering; Environment; Experimental Designs; Exudative age-related macular degeneration; Eye; Faculty; Fellowship; Fluorescein Angiography; Funding; Future; Gene Expression Profile; Genetic; Goals; Grant; Growth; Human; Hypersensitivity; Image; Imaging Techniques; Immune; Immune system; Immunoglobulin Fragments; Immunologic Receptors; In Vitro; Inflammation; Interleukins; Invaded; Investigation; Journals; K-Series Research Career Programs; Kentucky; Knowledge; Laboratories; Lead; Legal; Legal Blindness; Lesion; Leukocytes; Ligands; Malignant Neoplasms; Maps; Mediating; Medicine; Mentors; Methods; Molecular; Molecular Profiling; Molecular Target; Mus; Nature; Nonexudative age-related macular degeneration; Ophthalmic examination and evaluation; Ophthalmology; Outcome; Oxidative Stress; Pathogenesis; Pathologic Processes; Pathway interactions; Patient Care; Patients; Pattern; Physicians; Positioning Attribute; Prevalence; Principal Investigator; Process; Progressive Disease; Quality of life; Regulation; Relative (related person); Reporting; Research; Research Personnel; Research Project Grants; Research Training; Retina; Retinal Diseases; Risk Factors; Role; Running; Safety; Scientist; Sensitivity and Specificity; Signal Pathway; Signal Transduction; Signaling Molecule; Specialist; Specimen; Staging; Structure of retinal pigment epithelium; Sum; Surface; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Toxicology; Training; Training Programs; Transgenic Mice; Treatment Efficacy; Treatment Failure; United States; Universities; Uveal Melanoma; Vascular Diseases; Vascular Endothelial Growth Factor A; Vision; Visual; Work; allergic response; base; career; career development; cell type; chemokine; chemokine receptor; cost; cytokine; cytotoxicity; design; disorder of macula of retina; experience; imaging probe; immune activation; improved; in vivo; insight; molecular marker; mouse model; nanocrystal; neutralizing antibody; next generation; normal aging; ocular angiogenesis; pre-clinical; prevent; professor; programs; research study; response; skills; small molecule; therapeutic development; therapeutic target; vision science

DESCRIPTION (provided by applicant): The candidate is applying for a Mentored Clinical Scientist Research Career Development Award (K08) to support a 5 year research career training program that will significantly bolster his transition to faculty independence as a fellowship trained clinician-scientist specializing in vitreoretinal and macular diseases. The rigorous training program has been designed with extensive input and unyielding support from the candidate's mentor, co-mentor, chairman, and advisory committee. All training will take place in the excellent scientific and academic environment of the University of Kentucky, Department of Ophthalmology and Visual Sciences which includes an ocular angiogenesis research consortium consisting of four independent investigators. The applicant will spend the first 3 years of the program as a Research Assistant Professor and Clinical Fellow. The specific design of the fellowship is precisely detailed in the Career Development section and accompanied by a very strong institutional commitment that allows the candidate at least 80% effort performing research and 20% performing clinical duties. After completion of the fellowship, the candidate will transition to a full-time faculty position as Assistant Professor at University of Kentucky with the same institutional commitment of 80% research and 20% clinical effort. The long-term goal of the award is to offer the candidate the critical career development support to establish a pathway to faculty independence that will extensively train him as a biomedical researcher, confident and masterful specialist in the diagnosis and treatment of vitreoretinal and macular diseases, and leading academician. The candidate aims to have an independent laboratory up and running within the initial 12-18 months of the award period in order to gain early independence with his research project and develop critical principal investigator skills with guidance from his established mentors and advisory committee. The research plan has been devised by the candidate and his mentors and aims to extend his scientific expertise beyond basic vascular biology with a rich experience to develop new techniques and to utilize such methods in experimental designs to obtain critical data that expand his current fund of knowledge in order to yield fundamental insights on endothelial cell dysregulation, immuno-modulation in vascular growth, and therapeutic targets in neovascular age-related macular degeneration (AMD). AMD is a devastating blinding disease that affects as many as 10 million Americans, a number that rivals the prevalence of all cancers combined and is unfortunately expected to double by 2020. The overwhelming cause of severe vision loss in AMD is choroidal neovascularization (CNV), the growth of abnormal blood vessels beneath the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial growth factor (VEGF)-A, the majority of patients do not regain functional vision, and a significant fraction progress to legal blindness. This treatment failure is attributed to the frequent clinical situation in which patients present to eye physicians after vision is already lost and irreversible structural and functional tissue damage has already occurred. Moreover, while patients with AMD often undergo at least one or more dilated eye examinations per year, the physician is often not able to detect CNV before it grows beneath the retina and wreaks havoc. Fortunately, there is an exciting development that may provide the first available technique for detecting incipient CNV in patients with AMD thereby allowing for earlier detection and treatment to prevent loss of vision and quality of life. This discovery was recently reported in the journal Nature and described as the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009). It is an immune receptor called chemokine receptor 3 (CCR3) that is involved in allergic response and recruitment of white blood cells but may also be found on inflamed and growing blood vessels. The identification of CCR3 as a molecular signature has opened a gateway to a new understanding in vascular disease in AMD. CCR3 expression is found on the surface of the specialized endothelial cells that line the abnormal blood vessels. In this proposal, rigorous basic science investigations of the cellular circuitry that mediates this pathogenic switch will be explored in conjunction with the biological relationships between endothelial cell dysregulation, aging, immune activation, and oxidative stress. The initial aim of the study is to decipher how these established AMD risk factors regulate the progression of disease through chemokine and other immune signaling pathways in order to develop appropriately targeted diagnostics and therapeutics that will enable clinicians to offer improved care of patients suffering from AMD. A second aim focuses specifically on CCR3 biology with scientific exploration of its pathogenetic induction, expression patterns and signaling effects during endothelial cell dysregulation in neovascular AMD. In a final aim, optimized fluorescent CCR3- targeting probes will be engineered and applied to pre-clinical animal models of CNV and human cellular toxicology studies in order to obtain necessary data to proceed with future clinical studies. These specific experimental aims will provide fundamental insights into the modulatory function of the immune system, chemokine signaling, and the role of CCR3 as a molecular switch during the endothelial cell dysregulation that heralds vision loss in neovascular AMD.

描述（由申请人提供）：候选人正在申请指导临床科学家研究职业发展奖（K08），以支持为期 5 年的研究职业培训计划，该计划将显着促进他作为一名受过奖学金培训的临床医生科学家向教师独立的过渡。玻璃体视网膜和黄斑疾病。严格的培训计划是在候选人的导师、共同导师、主席和咨询委员会的广泛投入和坚定支持下设计的。所有培训都将在肯塔基大学眼科和视觉科学系优良的科学和学术环境中进行，其中包括由四名独立研究人员组成的眼部血管生成研究联盟。申请人将在该项目的前 3 年担任研究助理教授和临床研究员。该奖学金的具体设计在职业发展部分进行了详细说明，并附有非常强有力的机构承诺，允许候选人至少 80% 的精力用于研究，20% 的精力用于履行临床职责。完成奖学金后，候选人将过渡到肯塔基大学担任全职助理教授，并承担同样的机构承诺，即 80% 的研究和 20% 的临床工作。该奖项的长期目标是为候选人提供关键的职业发展支持，以建立一条通往教师独立的途径，将他广泛培训为一名生物医学研究员、玻璃体视网膜和黄斑疾病诊断和治疗方面自信而熟练的专家，和首席院士。候选人的目标是在奖励期的最初 12-18 个月内建立并运行一个独立的实验室，以便尽早独立完成他的研究项目，并在他既定的导师和咨询委员会的指导下培养关键的首席研究员技能。该研究计划是由候选人和他的导师设计的，旨在将他的科学专业知识扩展到基础血管生物学之外，并拥有丰富的经验来开发新技术，并在实验设计中利用这些方法来获取关键数据，从而扩展他当前的知识储备为了获得关于内皮细胞失调、血管生长的免疫调节以及新生血管性年龄相关性黄斑变性 (AMD) 治疗目标的基本见解。 AMD 是一种毁灭性的致盲疾病，影响着多达 1000 万美国人，这一数字可与所有癌症的患病率总和相媲美，不幸的是预计到 2020 年将翻一番。AMD 严重视力丧失的主要原因是脉络膜新生血管 (CNV)，视网膜下方异常血管的生长。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功能性视力，并且相当一部分患者进展为法定失明。这种治疗失败的原因是临床上经常出现这样的情况：患者在视力已经丧失并且已经发生不可逆的结构和功能组织损伤后才去看眼科医生。此外，虽然 AMD 患者每年至少要接受一次或多次散瞳检查，但医生往往无法在 CNV 生长到视网膜下方并造成严重破坏之前检测到它。幸运的是，一项令人兴奋的进展可能会提供第一个可用的技术来检测 AMD 患者的早期 CNV，从而实现早期检测和治疗，以防止视力丧失和生活质量下降。这一发现最近发表在《自然》杂志上，并被描述为第一个针对人类 CNV 的分子标记（Takeda 等人，Nature 2009）。它是一种称为趋化因子受体 3 (CCR3) 的免疫受体，参与过敏反应和白细胞募集，但也可能存在于发炎和生长的血管上。 CCR3 作为分子特征的鉴定为对 AMD 血管疾病的新认识打开了大门。 CCR3 表达存在于异常血管内衬的特殊内皮细胞的表面。在该提案中，将对介导这种致病开关的细胞回路进行严格的基础科学研究，并结合内皮细胞失调、衰老、免疫激活和氧化应激之间的生物学关系进行探索。该研究的最初目的是破译这些已确定的 AMD 危险因素如何通过趋化因子和其他免疫信号通路调节疾病的进展，以便开发适当的有针对性的诊断和治疗方法，使临床医生能够为患有 AMD 的患者提供更好的护理。第二个目标特别关注 CCR3 生物学，科学探索其在新生血管性 AMD 内皮细胞失调过程中的发病诱导、表达模式和信号传导效应。最终目标是，优化荧光 CCR3 靶向探针将被设计并应用于 CNV 和人类细胞毒理学研究的临床前动物模型，以获得必要的数据以进行未来的临床研究。这些具体的实验目标将为免疫系统的调节功能、趋化因子信号传导以及 CCR3 作为分子开关在内皮细胞失调（预示新生血管性 AMD 视力丧失）过程中的作用提供基础见解。