Role in Myopia Development of Retinal Pigment Epithelium - A New Therapeutic Targ

视网膜色素上皮在近视发展中的作用——一种新的治疗目标

• 批准号: 8737905
• 负责人: Yan Zhang
• 金额: $ 14.97万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737905
• 关键词: Academia; Affect; Animal Model; Animals; Apical; Apomorphine; Award; Blood; Bone Morphogenetic Protein Gene; Bone Morphogenetic Proteins; California; Cell Culture Techniques; Cell Differentiation process; Cells; Cellular biology; Choroid; Clinical; Cloning; Communities; Data; Development; Developmental Biology; Discipline; Disease; Doctor of Philosophy; Dopamine; Dopamine Agonists; Electrophysiology (science); Electroporation; Electroretinography; Embryonic Development; Environment; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Eye; Eye diseases; Family; Frequencies; Funding; Gene Expression; Genes; Goals; Grant; Growth; Growth Factor; Harvest; Human; Image; Immunohistochemistry; In Vitro; Individual; Investigation; Journals; K-Series Research Career Programs; Knowledge; Measurement; Measures; Mediating; Medicine; Mentors; Mentorship; Modeling; Molecular Biology; Morphogenesis; Myopia; Ophthalmology; Optic Nerve; Optical Coherence Tomography; Optics; Outcome; Paper; Physiology; Play; Population; Positioning Attribute; Preparation; Prevalence; Production; Productivity; Protein Family; Protein Secretion; Publications; Refractive Errors; Regulation; Research; Research Personnel; Research Proposals; Retina; Retinal; Risk; Role; San Francisco; Scanning; Scientist; Senior Scientist; Severities; Signal Transduction; Structure of retinal pigment epithelium; Techniques; Technology; Testing; Therapeutic Intervention; Therapeutic Studies; Time; Tissues; Training; Translational Research; Ultrasonography; United States National Institutes of Health; Universities; Virus; Western Blotting; age group; bone; bone morphogenetic protein 2; career; career development; economic implication; experience; fetal; follow-up; gene therapy; immunocytochemistry; in vitro Model; in vivo; knock-down; lens; member; new therapeutic target; novel; novel therapeutics; prevent; professor; programs; protein expression; public health relevance; receptor; research study; response; skills; social implication; subretinal injection; vision science

DESCRIPTION (provided by applicant): The Mentored Clinical Scientist Research Career Development Award (K08) candidate, Yan Zhang, earned her clinical degrees in Medicine and Ophthalmology, and she is currently pursuing her Ph.D. degree in the Vision Science Program at University of California, Berkeley, which will be completed in the Spring 2013. She has already one publication in a high profile journal from the latter research, with 2 more papers soon to be submitted, demonstrating both good productivity and research drive. As the next step towards a career as an independent clinician scientist in academia, Dr. Zhang is applying for a K08 career award to obtain advanced training - to further expand her scientific knowledge and biomedical technical skills through investigations into the roles of retinal pigment epithelium (RPE) and bone morphogenetic proteins (BMPs) in eye growth regulation and myopia development, with the RPE targeted in related exploratory studies of gene therapy for myopia treatment. Over the course of her studies to-date, Dr. Zhang has received broad training in many of the disciplines required for successfully executing her proposed project. She proposed to cover remaining deficiencies with additional coursework and hands-on training during the 5-year training period of the K award for which she is applying. Thus at the end of this 5-year career development award Dr. Zhang should be well prepared for a career as an independent researcher, successfully competing for research funds. The proposed study will be conducted primarily under the mentorship of Dr. Christine Wildsoet, who is a well- known leading scientist in the field of myopia and eye growth regulation. Myopia, or nearsightedness, is one of most common refractive errors in humans and significantly contributes to the global burden of eye disease. It is the product of eyes growing excessively long. The prevalence and the severity of myopia have risen worldwide during the past several decades, stimulating increased research into the underlying mechanisms, an essential step in developing effective anti-myopia therapies. Previous studies have suggested that early eye growth regulation is largely localized to eye itself. The RPE is known to be a component of the blood-retina barrier, with critical roles in maintaining normal retinal and choroidal functions. Recent research findings, mostly from the Wildsoet lab and much of it belongs to Dr. Zhang, suggest that it also plays an essential role in the regulation of eye growth. The proposal focuses on the role of RPE in myopia development and as a potential target for myopia therapy, with 3 specific aims: (1) to investigate the role of RPE-derived bone morphogenetic proteins (BMPs) in eye growth regulation; (2) to investigate the effects of dopamine (DA) on RPE-BMP expression and secretion; (3) to investigate over-expression of BMPs in RPE as a potential gene therapy for myopia. Complementary experiments include in vivo animal studies, using the chick as an myopia model, and in vitro cell culture studies, using human fetal (hf) RPE as a model, exploiting Dr. Zhang's experience with both models. In vivo structural and functional measurements will use advanced technologies, including high frequency A-scan ultrasonography, spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG). A variety of molecular and cell biology techniques will also be used including cloning, real-time PCR, Western blot, ELISA, and immunohistochemistry. Techniques most commonly encountered in ocular gene therapy research, including electroporation and subretinal injection, will also be employed. The proposed research will be conducted under the co-mentorship of Dr. Jeanette Hyer from UC San Francisco, who is an expert in developmental biology, with a focus on chick embryogenesis. Three senior scientists have also agreed to serve as consultants on her project: Professor Lawrence Rizzolo (Yale University) and Dr. Sheldon Miller (NEI/NIH), who are experts in RPE physiology and electrophysiology, and Professor Kunxin Luo (UC Berkeley), whose research focus is the TGF-¿ family including BMPs and their roles in cell differentiation, tissue morphogenesis, and extracellular matrix production. UC Berkeley and UC San Francisco offer world-class research environments and support for the preparation and training of young scientists for independent research careers.

描述（由申请人提供）：导师临床科学家研究职业发展奖（K08）候选人张艳获得了医学和眼科临床学位，目前正在攻读博士学位。她在加州大学伯克利分校的视觉科学项目获得了博士学位，该项目将于 2013 年春季完成。她已经在一份备受瞩目的期刊上发表了一篇关于后者研究的论文，并且即将提交另外 2 篇论文，展示了良好的生产力和研究动力。作为学术界独立临床科学家职业生涯的下一步，张博士正在申请K08职业奖以获得高级培训——通过研究视网膜色素上皮（RPE）和骨形态发生蛋白（BMP）在眼睛生长调节和近视发展中的作用，进一步扩展她的科学知识和生物医学技术技能，其中RPE针对基因治疗的相关探索性研究 近视治疗。在迄今为止的学习过程中，张博士接受了成功执行其拟议项目所需的许多学科的广泛培训。她提议在她申请的 K 奖的 5 年培训期内通过额外的课程和实践培训来弥补剩余的缺陷。因此，在这五年的职业发展奖结束时，张博士应该为作为一名独立研究员的职业生涯做好充分准备，成功竞争研究基金。拟议的研究将主要在 Christine Wildsoet 博士的指导下进行，她是近视和眼睛生长调节领域著名的领先科学家。近视是人类最常见的屈光不正之一，严重加重了全球眼部疾病的负担。这是眼睛过长的产物。过去几十年来，全球范围内近视的患病率和严重程度不断上升，刺激了对其潜在机制的更多研究，这是开发有效的抗近视疗法的重要一步。先前的研究表明，早期眼睛生长调节很大程度上局限于眼睛本身。众所周知，RPE 是血视网膜屏障的组成部分，在维持正常的视网膜和脉络膜功能方面发挥着关键作用。最近的研究结果（大部分来自 Wildsoet 实验室，其中大部分属于张博士）表明，它在调节眼睛生长方面也发挥着重要作用。该提案重点关注RPE在近视发展中的作用以及作为近视治疗的潜在靶点，有3个具体目标：（1）研究RPE衍生的骨形态发生蛋白（BMP）在眼睛生长调节中的作用； (2)探讨多巴胺(DA)对RPE-BMP表达和分泌的影响； (3) 研究RPE中BMP的过度表达作为近视的潜在基因治疗。补充实验包括体内动物研究（使用小鸡作为近视模型）和体外细胞培养研究（使用人类胎儿（hf）RPE作为模型），利用张博士在这两种模型方面的经验。体内结构和功能测量将使用先进技术，包括高频 A 扫描超声检查、频域光学相干断层扫描 (SD-OCT) 和视网膜电图检查 (ERG)。还将使用各种分子和细胞生物学技术，包括克隆、实时 PCR、蛋白质印迹、ELISA 和免疫组织化学。还将采用眼部基因治疗研究中最常见的技术，包括电穿孔和视网膜下注射。拟议的研究将在加州大学旧金山分校的 Jeanette Hyer 博士的共同指导下进行，她是发育生物学专家，重点研究鸡胚胎发生。三位资深科学家也同意担任她的项目顾问：Lawrence Rizzolo 教授（耶鲁大学）和 Sheldon Miller 博士（NEI/NIH），他们是 RPE 生理学和电生理学专家，以及 Kunxin Luo 教授（加州大学伯克利分校），他的研究重点是 TGF-¿ 家族，包括 BMP 及其在细胞分化、组织形态发生和细胞分化中的作用。 细胞外基质的产生。加州大学伯克利分校和加州大学旧金山分校提供世界一流的研究环境，并为年轻科学家独立研究生涯的准备和培训提供支持。