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

摘要 这笔K08助学金的目的是让赵丹尼博士、医学博士和博士博士获得必要的科学培训 和专业技能，成为年龄相关性黄斑领域的独立调查者 退行性变(AMD)。非渗出性AMD的一个病理特征是存在玻璃体、脂肪沉积。 位于视网膜色素上皮(RPE)下方，导致RPE萎缩和感光细胞死亡。 玻璃体生物发生和RPE萎缩的机制尚不清楚，目前有 没有治疗方法可以延缓非渗出性AMD的进展。长链多不饱和酸(LC- 多不饱和脂肪酸)通过生化和流行病学研究与AMD的发病机制有关； 然而，多不饱和脂肪酸促进AMD的分子机制尚不清楚。我们的 初步数据表明，ELOVL2是LC-PUFAs延伸的关键酶，在 斑疹生物发生学。我们的中心假设是视网膜色素上皮中的ELOVL2活性 防止酒渣样沉积物的形成，ELOVL2延伸的omega-3产物负责 为了达到这个效果。我们将通过以下具体目标来检验这一假设：1)表征 缺乏ELOVL2酶活性的RPE的代谢和分子变化决定了 ELOVL2在RPE中的表达是通过细胞特异性拯救形成玻璃膜样沉积所必需的 体内实验，以及3)剖析ELOVL2延伸的omega-3和omega-6产物的作用 通过对ELOVL2突变动物进行脂质补充。我们提出的研究具有重要意义，因为 他们描述了一种新的基因和形成玻璃疱疹的途径。积极的翻译影响是 治疗非渗出性AMD的新治疗策略的潜在开发。为了实现这一目标， 赵博士在加州大学圣地亚哥分校组建了一支由乔纳森·林博士医学博士组成的杰出指导团队。 博士，视网膜退行性疾病专家，多洛塔·斯科沃朗斯卡-克劳奇克博士， 眼科疾病衰老的分子机制。这项工作由一名外部临床医生--科学家进行补充 具有黄斑变性研究和临床医生-科学家职业发展经验的委员会。 该培训计划的主要组成部分包括：1)获取科学和技术专业知识，以使用 研究玻璃疣生物发生的小鼠模型2)正规的授课课程：赠款书写、小鼠遗传学和 脂质生物学3)生成R01提交的初步数据，以及4)计划过渡到 通过师徒关系实现独立。这项工作发生在杰出的科学环境中， 加州大学圣迭戈分校和眼科拥有世界级的设施， 培养出成功的临床医生和科学家。结合他在玻璃体视网膜的临床训练 外科，这一培训计划将使赵医生成为一名领先的临床医生-科学家，拥有独立的 R01资助的研究计划专注于寻找治疗黄斑变性的新疗法。

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.