Dissecting the role of ELOVL2 in Drusen Biogenesis and Age Related Macular Degeneration

剖析 ELOVL2 在玻璃疣生物发生和年龄相关性黄斑变性中的作用

• 批准号: 9805092
• 负责人: DANIEL L CHAO
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805092
• 关键词: Acids; Age; Age related macular degeneration; Aging; Animals; Atrophic; Biochemical Epidemiology; Biogenesis; Biology; Blindness; Cell Culture Techniques; Cells; Cessation of life; Choroid; Clinical; Complement; Complement Activation; Data; Deposition; Development; Dietary intake; Doctor of Medicine; Doctor of Philosophy; Drusen; Electroretinography; Environment; Enzymes; Epidemic; Eye; Eye diseases; Fatty Acids; Funding; Generations; Genes; Genetic; Goals; Grant; Human; Individual; Knock-in Mouse; Lead; Link; Lipids; Macular degeneration; Measures; Mediating; Mentors; Mentorship; Metabolic; Molecular; Mus; Nonexudative age-related macular degeneration; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Operative Surgical Procedures; Ophthalmology; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Photoreceptors; Play; Polyunsaturated Fatty Acids; Public Health; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Risk; Role; Scientist; Structure of retinal pigment epithelium; Supplementation; Technical Expertise; Testing; Training; Work; Writing; age related; base; career development; cell type; docosahexaenoylascorbic acid; epidemiology study; experience; experimental study; geographic atrophy; in vitro Assay; in vitro activity; in vivo; intravitreal injection; lipid metabolism; macula; molecular marker; mouse model; mutant; novel; novel therapeutics; overexpression; prevent; programs; promoter; skills; success; translational impact; treatment strategy; vector

ABSTRACT The goal of this K08 grant is to allow Dr. Daniel Chao, M.D., Ph.D. to obtain the necessary scientific training and professional skills to become an independent investigator in the field of age-related macular degeneration (AMD). A pathologic hallmark of nonexudative AMD is the presence of drusen, lipid deposits below the retinal pigment epithelium (RPE), which leads to RPE atrophy and photoreceptor death. Mechanisms underlying drusen biogenesis and RPE atrophy are poorly understood, and currently there is no therapy which slows the progression of nonexudative AMD. Long chain polyunsaturated acids (LC- PUFAs) have been implicated in AMD pathogenesis through biochemical and epidemiology studies; however the molecular mechanisms by which PUFAs contribute to AMD is poorly understood. Our preliminary data suggests that ELOVL2, a key enzyme in elongation of LC-PUFAs, plays a key role in drusen biogenesis. Our central hypothesis is that ELOVL2 activity in the retinal pigment epithelium prevents drusen-like deposit formation, and that omega-3 products of ELOVL2 elongation are responsible for this effect. We will test this hypothesis through the following specific aims: 1) Characterization of metabolic and molecular changes in RPE lacking ELOVL2 enzymatic activity 2) Determine the extent that ELOVL2 expression in the RPE is required for drusen-like deposit formation through cell specific rescue experiments in vivo, and 3) Dissect the roles of omega-3 and omega-6 products of ELOVL2 elongation through lipid supplementation in ELOVL2 mutant animals. Our proposed studies are significant because they characterize a novel gene and pathway in drusen formation. The positive translational impact is the potential development of novel therapeutic strategies for treatment of nonexudative AMD. To achieve this, Dr. Chao has assembled an exceptional mentoring team at UCSD consisting of Dr. Jonathan Lin, M.D., Ph.D. an expert in retinal degenerative diseases, and Dr. Dorota Skowronska-Krawczyk, PhD, an expert on molecular mechanisms of aging in eye diseases. This is complemented by an external clinician-scientist committee with experience in macular degeneration research and clinician-scientist career development. Key components of this training plan include 1) acquisition of scientific and technical expertise to use the mouse model to study drusen biogenesis 2) formal didactic courses in grant writing, mouse genetics, and lipid biology 3) generation of preliminary data for an R01 submission, and 4) planned transition to independence through mentorship. This work takes place within the outstanding scientific environment and world class facilities at UCSD and the department of ophthalmology, which has a strong track record of producing successful clinician-scientists. Combined with his training in clinical training in vitreoretinal surgery, this training plan will allow Dr. Chao to become a leading clinician-scientist with an independent R01- funded research program focused on identifying new therapies for macular degeneration.

摘要 这项K 08资助的目标是让丹尼尔赵博士，医学博士，博士获得必要的科学训练 和专业技能，成为一个独立的研究人员在该领域的年龄相关性黄斑 退行性变（AMD）。非渗出性AMD的病理标志是玻璃疣、脂质沉积 在视网膜色素上皮（RPE）下方，这导致RPE萎缩和感光细胞死亡。 玻璃疣生物发生和RPE萎缩的潜在机制知之甚少，目前有 没有减缓非渗出性AMD进展的治疗。长链多不饱和酸（LC- 通过生物化学和流行病学研究，PUFA）与AMD发病机制有关; 然而，人们对PUFA导致AMD的分子机制知之甚少。我们 初步数据表明，LC-PUFAs延伸中的关键酶LC-VL 2在LC-PUFAs延伸中起关键作用， 玻璃疣的生物成因我们的中心假设是视网膜色素上皮细胞中的HPVL 2活性 防止玻璃霜样存款形成，并且，EMPVL 2延伸的ω-3产物负责 为了这个效果。我们将通过以下具体目标来检验这一假设：1）表征 2）确定缺乏BLVL 2酶活性的RPE的代谢和分子变化的程度， RPE中的CD 3VL 2表达是通过细胞特异性拯救形成玻璃状存款所必需的 体内实验，以及3）剖析ω-3和ω-6产物在BMPVL 2延伸中的作用 通过脂质补充剂在HPVL 2突变动物中。我们提出的研究是重要的，因为 它们表征了玻璃疣形成中的新基因和途径。积极的翻译影响是 潜在的开发新的治疗策略，用于治疗非渗出性AMD。为了实现这一点， 博士Chao在UCSD组建了一支由Jonathan Lin博士，医学博士， 博士视网膜退行性疾病专家Dorota Skowronska-Krawczyk博士， 眼科疾病中衰老的分子机制。这是由外部临床医生科学家补充 委员会在黄斑变性研究和临床医生-科学家职业发展方面的经验。 该培训计划的主要组成部分包括：（1）获得科学和技术专门知识， 研究玻璃疣生物发生的小鼠模型2）正式的教学课程，包括资助写作、小鼠遗传学和 脂质生物学3）生成R 01提交的初步数据，以及4）计划过渡到 通过指导实现独立。这项工作是在杰出的科学环境中进行的， 世界一流的设施，在加州大学圣地亚哥分校和眼科，其中有一个强大的跟踪记录， 培养成功的临床科学家并结合自己在玻璃体视网膜临床培训的体会 手术，这个培训计划将使赵博士成为一个领先的临床科学家与独立的 R 01资助的研究项目专注于确定黄斑变性的新疗法。