Endothelial Cell Dysregulation in Neovascular AMD

描述(由申请人提供)：应聘者正在申请导师临床科学家研究职业发展奖(K08)，以支持一项为期5年的研究职业培训计划，该计划将显著促进他向教师独立性的过渡，成为一名受过研究员培训的临床医生兼科学家，专门从事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不移的支持下设计的。所有培训将在肯塔基大学眼科和视觉科学系良好的科学和学术环境中进行，其中包括一个由四名独立研究人员组成的眼血管生成研究联盟。申请者将在该项目的前三年担任研究助理教授和临床研究员。奖学金的具体设计在职业发展一节中有确切的详细说明，并伴随着非常强大的机构承诺，允许候选人至少80%的精力进行研究，20%的时间履行临床职责。完成奖学金后，候选人将过渡到肯塔基大学助理教授的全职教职，承担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道路，这将广泛地培养他成为一名生物医学研究员，在玻璃体视网膜和黄斑疾病的诊断和治疗方面自信而精通的专家，以及领先的院士。候选人的目标是在获奖期的最初12-18个月内建立并运行一个独立的实验室，以便早日实现研究项目的独立，并在其既定导师和咨询委员会的指导下发展关键的主要研究人员技能。该研究计划由候选人和他的导师设计，旨在将他的科学专长扩展到具有丰富经验的基础血管生物学之外，以开发新技术，并在实验设计中利用这些方法获得关键数据，以扩大他目前的知识基金，以便对血管内皮细胞失调、血管生长中的免疫调节以及新生血管年龄相关性黄斑变性(AMD)的治疗目标产生基本见解。AMD是一种毁灭性的致盲疾病，影响着多达1000万美国人，这个数字与所有癌症的患病率总和相当，不幸的是，预计到2020年将翻一番。AMD严重视力丧失的压倒性原因是脉络膜新生血管(CNV)，即视网膜下异常血管的生长。尽管最近批准了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功能性视力，还有相当一部分患者进展到合法失明。这种治疗失败是由于患者在视力已经丧失后出现在眼科医生面前的频繁的临床情况，并且已经发生了不可逆转的结构和功能组织损伤。此外，虽然AMD患者通常每年至少接受一次或多次扩眼检查，但医生往往无法在CNV生长到视网膜下并造成严重破坏之前检测到它。幸运的是，有一项令人兴奋的发展，它可能提供第一种可用于检测AMD患者早期CNV的技术，从而允许更早地发现和治疗，以防止视力和生活质量的丧失。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。《自然》2009年)。它是一种名为趋化因子受体3(CCR3)的免疫受体，参与过敏反应和白细胞的募集，但也可能在发炎和生长的血管上发现。CCR3作为一种分子标志物的发现，为人们对AMD血管疾病的新认识打开了大门。CCR3表达在排列在异常血管内的特殊内皮细胞的表面。在这项建议中，将结合内皮细胞失调、衰老、免疫激活和氧化应激之间的生物学关系来探索介导这种致病开关的细胞电路的严格基础科学研究。这项研究的最初目的是破译这些已确立的AMD风险因素如何通过趋化因子和其他免疫信号途径调节疾病的发展，以便开发适当的有针对性的诊断和治疗方法，使临床医生能够改善AMD患者的护理。第二个目标主要集中在CCR3生物学上，科学探索其在新生血管性AMD血管内皮细胞失调过程中的致病诱导、表达模式和信号作用。在最终目标中，优化的荧光CCR3靶向探针将被设计并应用于临床前CNV动物模型和人类细胞毒理学研究，以获得进行未来临床研究所需的数据。这些特定的实验目标将为免疫系统的调节功能、趋化因子信号以及CCR3在血管内皮细胞失调中作为分子开关的作用提供基本的见解，内皮细胞失调预示着新生血管性AMD的视力丧失。

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.