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: 8568409
• 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/8568409
• 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

Zhang Y. Role in Myopia Development of Retinal Pigment Epithelium - A New Therapeutic Target ? Project Summary 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.

Zhang Y.在视网膜色素上皮的近视发展中的作用 - 一种新的治疗靶点？ 项目摘要 指导的临床科学家研究职业发展奖（K08）候选人Yan Zhang赢得了她 医学和眼科的临床学位，她目前正在攻读博士学位。视觉学位 加州大学伯克利分校的科学课程将于2013年春季完成。 后来的研究中已经有一本著名杂志的出版物，很快还有另外两篇论文 提交，证明了良好的生产力和研究驱动力。作为迈向职业的下一步 Zhang博士在学术界的独立临床科学家正在申请K08职业奖，以获得高级 培训 - 通过调查进一步扩大她的科学知识和生物医学技术技能 进入视网膜色素上皮（RPE）和骨形态发生蛋白（BMP）的作用 调节和近视发展，RPE针对基因治疗的相关探索性研究 近视治疗。张博士在她的学习至今已有很多方面接受了广泛的培训 成功执行她建议的项目所需的学科。她建议掩盖剩余的 在K的5年培训期内，缺陷以及其他课程和动手培训 她正在申请的奖项。在这个5年职业发展奖的结束时，张博士应该 为作为独立研究人员的职业做好准备，成功争夺研究基金。 拟议的研究将主要是在克里斯汀·怀尔德索特（Christine Wildsoet）博士的心态下进行的。 近视领域的知名领先科学家和眼睛生长调节。近视或近视是一个 在人类中最常见的折射率中，并显着促进了全球眼睛疾病的灼伤。 它是眼睛生长长的产物。近视的患病率和严重程度已经上升 在过去的几十年中，全世界在全球范围 开发有效的抗果皮疗法的重要步骤。先前的研究表明早期眼睛 生长调节在很大程度上本身就本地化了。 RPE已知是血液retina的组成部分 障碍，在维持正常残留和脉络膜功能方面具有关键作用。最近的研究发现， 主要来自Wildsoet实验室，其中大部分属于Zhang博士，这表明它在 眼睛生长的调节。该提案侧重于RPE在近视发展中的作用，并作为 近视治疗的潜在靶标，具有3个特定目的：（1）研究RPE衍生的骨骼的作用 眼睛生长调节中的形态发生蛋白（BMP）； （2）研究多巴胺（DA）对 RPE-BMP表达和分泌； （3）研究RPE中BMP作为潜在基因的过表达 近视治疗。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，利用张博士的 有两种模型的经验。体内结构和功能测量将使用先进的技术， 包括高频A扫描超声检查，光谱域光学相干断层扫描（SD-OCT） 和电子模拟（ERG）。还将使用各种分子和细胞生物学技术 克隆，实时PCR，Western印迹，ELISA和免疫组织化学。技术最常见 在包括电穿孔和视网膜下注射在内的眼基因治疗研究中遇到的也将是 雇用。拟议的研究将在UC的Jeanette Hyer博士的同学下进行 旧金山是发育生物学专家，重点是雏鸡胚胎发生。三个大四 科学家还同意担任其项目的顾问：劳伦斯·里佐洛教授（耶鲁大学） RPE生理学和电生理学专家的Sheldon Miller博士（Nei/NIH）和教授 Kunxin Luo（UC Berkeley），其研究重点是TGF-®家族，包括BMP及其在细胞中的作用 分化，组织形态发生和细胞外基质产生。加州大学伯克利分校和加州大学旧金山加州大学 提供世界一流的研究环境，并为年轻科学家的准备和培训提供支持 独立的研究事业。