In Vivo Modeling of Mitochondrial Complex I Deficiency in Retinal Ganglion Cells

视网膜神经节细胞线粒体复合物 I 缺陷的体内建模

• 批准号: 10329943
• 负责人: Sidney M Gospe
• 金额: $ 17.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329943
• 关键词: Abnormal Cell; Affect; Anaerobic Bacteria; Animal Model; Animals; Ataxia; Autosomal Dominant Optic Atrophy; Axon; Biochemical; Biological Assay; Biometry; Blindness; Cell Death; Cell Respiration; Cells; Cellular Metabolic Process; Cessation of life; Clinical; Clinical Research; Complex; Cre lox recombination system; Development; Development Plans; Disease; Doctor of Philosophy; Electrophysiology (science); Ensure; Environment; Enzymes; Faculty; Fellowship; Functional disorder; Funding; Genes; Genetic; Heart failure; Heritability; Histologic; Hydroxylation; Hypoxia; Immersion; Impairment; Induction of Apoptosis; Investments; Ischemic Optic Neuropathy; Knock-out; Knockout Mice; Lead; Leber' s Hereditary Optic Neuropathy; Leigh Disease; Link; Longevity; Longitudinal Studies; Mediating; Mentors; Mentorship; Metabolic; Metabolism; Mitochondria; Mitochondrial complex I deficiency; Molecular; Mus; Muscle hypotonia; Mutation; NADH dehydrogenase (ubiquinone); Neurobiology; Ophthalmologist; Ophthalmology; Optic Atrophy; Optic Nerve; Optic Neuritis; Oxidative Phosphorylation; Oxidative Stress; Pathology; Patients; Pharmacology; Pharmacotherapy; Play; Positioning Attribute; Process; Procollagen-Proline Dioxygenase; Property; Publications; Reactive Oxygen Species; Reagent; Research; Research Personnel; Resistance; Resource Development; Respiratory Failure; Retina; Retinal Ganglion Cells; Role; Scientist; Signal Pathway; Signal Transduction; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxicology; Training; Translations; Ubiquitin; Ubiquitination; Universities; Up-Regulation; VHL gene; Work; anaerobic glycolysis; career development; conditional knockout; design; drug discovery; early childhood; effective therapy; experience; eye center; faculty research; genetic approach; human disease; human model; in vivo Model; insight; interest; meetings; mitochondrial dysfunction; mouse model; multicatalytic endopeptidase complex; new therapeutic target; optic nerve disorder; postnatal; protein complex; responsible research conduct; retinal axon; retinal ganglion cell degeneration; retinal neuron; small molecule inhibitor; transcription factor; ubiquitin-protein ligase; visual dysfunction

Candidate: The candidate is a MD/PhD-trained clinician-scientist and board-eligible ophthalmologist currently completing a neuro-ophthalmology fellowship, who will be promoted to Duke Eye Center faculty in July, 2017. His research interest relates to pathobiology and drug discovery in mitochondrial optic neuropathies, a class of blinding disease for which effective therapy does not currently exist. Career Development Plan: The candidate proposes to create a mouse model of retinal ganglion cell (RGC)-specific complex I deficiency, predicted to cause particularly rapid and severe RGC degeneration. The proposed research will allow the candidate to gain experience in animal modeling of human disease, biochemical and histological assays of mitochondrial dysfunction, and retinal electrophysiology. Animal models, reagents, and insights developed in this project will serve as the basis for an R01 proposal to be submitted by the candidate in his final year of K08 support. Specific didactic courses in neurobiology, drug discovery and translation, toxicology, and biostatistics, as well as departmental research seminars and advanced training in responsible conduct of research will be obtained during his K08 tenure, and the candidate will present his findings regularly at national meetings and submit his work for publication. Environment: The candidate’s mentoring team consists of accomplished faculty whose wide range of expertise will be utilized in specific components of the research plan. He will also benefit from informal mentorship and interactions with world-class clinical and research faculty in the Duke Eye Center and from immersion in the dynamic intellectual environment and career development resources available throughout the university. Significant departmental commitment and deep personal investment by the mentoring team will ensure that the candidate is well positioned to transition to an independent R01-funded investigator. Research: Mitochondrial dysfunction frequently results in vision loss from optic neuropathy that reflects the particular sensitivity of RGCs to impaired aerobic metabolism and increased oxidative stress. This application’s central hypotheses are that (1) mitochondria-related RGC degeneration is a cell-autonomous process and (2) RGC metabolism may therefore be manipulated to make these cells less susceptible to mitochondrial insults. Aim 1 will test the first hypothesis by creating a mouse with severe deficiency of mitochondrial complex I specifically in RGCs via conditional knockout of the subunit ndufs4. RGCs in these mice will be assessed for histological, electrophysiological, and metabolic abnormalities. Aim 2 tests the second hypothesis by augmenting Hif-1α signaling with complementary genetic and pharmacologic approaches and assessing whether biasing RGC metabolism toward anaerobic glycolysis makes RGCs resistant to mitochondrial dysfunction and could represent a viable therapeutic strategy.

候选人：候选人是经过医学博士/博士学位培训的临床医生科学家，并且符合董事会资格 眼科医生目前正在完成神经眼科奖学金，将晋升为杜克大学 2017 年 7 月任眼科中心教员。他的研究兴趣涉及病理生物学和药物发现 线粒体视神经病是一类致盲性疾病，有效治疗无法治愈 目前不存在。 职业发展计划：候选人提出创建小鼠视网膜神经节细胞模型 (RGC) 特异性复合物 I 缺乏症，预计会导致特别快速和严重的 RGC 拟议的研究将使候选人获得动物建模的经验。 人类疾病、线粒体功能障碍和视网膜的生化和组织学测定 该项目中开发的动物模型、试剂和见解将作为 候选人在 K08 支持的最后一年提交 R01 提案的基础。 神经生物学、药物发现和翻译、毒理学等方面的具体教学课程 生物统计学，以及部门研究研讨会和高级培训 在 K08 任期内将获得负责任的研究行为，并且候选人 将定期在全国会议上展示他的发现，并提交他的作品以供出版。 环境：候选人的指导团队由经验丰富的教师组成，他们的知识广泛 他还将在研究计划的具体部分中运用一系列专业知识。 受益于非正式的指导以及与世界一流的临床和研究人员的互动 在杜克眼科中心，沉浸在充满活力的知识环境和职业生涯中 整个大学都有大量的开发资源。 导师团队的深度个人投入将确保候选人的良好表现 定位于过渡为 R01 资助的独立调查员。 研究：线粒体功能障碍经常导致视神经病变导致视力丧失 反映了 RGC 对有氧代谢受损和增加的特殊敏感性 本申请的中心假设是 (1) 线粒体相关的 RGC。 变性是一个细胞自主过程，（2）因此可以操纵 RGC 代谢来 使这些细胞不易受到线粒体损伤的影响 目标 1 将检验第一个假设。 通过创建一只严重缺乏线粒体复合物 I 的小鼠，特别是在 RGC 中 将评估这些小鼠中 ndufs4 亚基的条件敲除的组织学、 目标 2 通过以下方式检验第二个假设。 通过互补的遗传和药理学方法增强 Hif-1α 信号传导， 评估 RGC 代谢偏向无氧糖酵解是否会使 RGC 产生耐药性 线粒体功能障碍，可能代表一种可行的治疗策略。

项目成果

Traumatic chiasmopathy following mild trauma in a patient with thyroid orbitopathy.

• DOI: 10.1016/j.ajoc.2021.101021
• 发表时间: 2021-03
• 期刊: American journal of ophthalmology case reports
• 作者: O'Sullivan ML;Gospe SM 3rd
• 通讯作者: Gospe SM 3rd