Endothelial Cell Dysregulation in Neovascular AMD

新生血管性 AMD 中的内皮细胞失调

• 批准号: 8531947
• 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/8531947
• 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 Intervention; 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的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，该计划将大大加强他作为奖学金培训的临床医生，专门针对内外疾病和黄斑疾病的研究生培训的临床医生，从而大大支持他向教职员工独立的过渡。严格的培训计划是由候选人的导师，联合董事长，董事长和咨询委员会的广泛投入和不屈不挠的支持设计的。所有培训都将在肯塔基大学，眼科和视觉科学系的优秀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。申请人将在该计划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部门精确详细介绍，并伴随着非常强大的机构承诺，该承诺使候选人至少有80％的努力进行研究和20％的临床职责。奖学金完成后，候选人将过渡到肯塔基大学的助理教授的全职教职员工，同样对80％的研究和20％的临床工作进行了同样的机构承诺。该奖项的长期目标是为候选人提供关键的职业发展支持，以建立通往教师独立性的途径，该途径将在诊断和治疗玻璃体视网膜和黄斑疾病的诊断和治疗方面广泛训练他为生物医学研究员，自信和精湛的专家，以及领先的院士。该候选人的目标是在奖励期的最初12-18个月内建立一个独立的实验室，以便在其研究项目中获得尽早独立，并在其既定导师和咨询委员会的指导下发展重要的首席研究员技能。 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变性（AMD）。 AMD是一种毁灭性的盲目疾病，影响了多达1000万美国人，这与所有癌症的普遍性相媲美，不幸的是，预计到2020年，AMD的严重视力丧失的压倒性原因是脉络膜新生血管形成（CNV），脉络膜新生血管形成（CNV），在视觉视野旁的异常血管的生长。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，但大多数患者不重新获得功能视力，并且对法律失明的分数很大。这种治疗失败归因于频繁的临床状况，在视力已经失去后，患者向眼科医生出现，并且已经发生了不可逆转的结构和功能性组织损伤。此外，尽管AMD患者每年通常至少进行一次或多次扩张的眼睛检查，但医生通常无法在CNV生长之前检测到CNV并造成严重破坏。幸运的是，有一个令人兴奋的开发项目可能会提供第一种可用的技术来检测AMD患者的初始CNV，从而允许早期检测和治疗以防止视力和生活质量的丧失。最近在《自然》杂志上报道了这一发现，并被描述为针对人CNV的第一个分子标记（Takeda等人自然，2009年）。这是一种称为趋化因子受体3（CCR3）的免疫受体，参与了白细胞过敏和募集，但也可能在发炎和生长的血管上发现。 CCR3作为分子签名的鉴定为AMD血管疾病的新理解打开了门户。 CCR3表达在排列异常血管的专用内皮细胞的表面上。在此提案中，将介导这种致病开关的细胞回路的严格基础科学研究与内皮细胞失调，衰老，免疫激活和氧化应激之间的生物学关系探索。该研究的最初目的是破译这些已建立的AMD危险因素如何通过趋化因子和其他免疫信号通路来调节疾病的进展，以开发适当的靶向诊断和治疗剂，从而使临床医生能够为患有AMD的患者提供改善的护理。第二个目的是专门针对CCR3生物学，以科学探索其致病性诱导，表达模式和在新生血管中内皮细胞失调期间的信号传导作用。在最终目标中，将设计优化的荧光CCR3靶向探针，并应用于CNV和人类细胞毒理学研究的临床前动物模型，以获取必要的数据以进行未来的临床研究。这些特定的实验目的将为免疫系统的调节功能，趋化因子信号传导以及CCR3作为内皮细胞失调期间的分子开关的作用提供基本见解，以预示新血管AMD中视力丧失。