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.

应聘者：应聘者是一名医学博士/博士学位的临床医生、科学家，并符合董事会资格 眼科医生目前正在完成神经眼科奖学金，他将晋升为杜克大学 2017年7月，眼科中心教职员工。他的研究兴趣与病理生物学和药物发现有关。 在线粒体视神经病变中，一类有效治疗的致盲疾病 当前不存在。 职业发展规划：应聘者建议建立视网膜神经节细胞的小鼠模型 (RGC)特异性复合体I缺乏，预计会导致特别迅速和严重的RGC 退化。拟议的研究将使候选人获得动物建模方面的经验 人类疾病，线粒体功能障碍的生化和组织学分析，以及视网膜 电生理学。在这个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的R01提案的基础。 神经生物学、药物发现和翻译、毒理学和 生物统计学，以及部门研究研讨会和高级培训 在他的K08任期内，将获得负责任的研究指导，候选人 将定期在国家会议上介绍他的发现，并提交他的作品供出版。 环境：候选人的指导团队由成就卓著的教职员工组成，他们的工作范围广泛 将在研究计划的具体组成部分中利用各种专门知识。他还将 受益于与世界级临床和研究人员的非正式指导和互动 在杜克眼科中心，从沉浸在动态的智力环境和职业生涯中 整个大学都有可用的发展资源。重要的部门承诺 而指导团队的深度个人投资将确保候选人的健康 定位于过渡到独立的R01资助的调查员。 研究：线粒体功能障碍经常导致视神经病变导致视力丧失 反映视网膜节细胞对有氧代谢受损和增加的特殊敏感性 氧化应激。这个应用程序的中心假设是(1)线粒体相关的RGC 退化是一个细胞自主的过程，(2)RGC的新陈代谢因此可以被操纵 使这些细胞不那么容易受到线粒体的侮辱。目标1将检验第一个假设 通过建立视网膜神经节细胞线粒体复合体I严重缺陷的小鼠 Ndufs4亚基的条件性敲除。这些小鼠的视网膜神经节细胞将被评估组织学， 电生理和代谢异常。Aim 2通过以下方式测试第二个假设 用互补的遗传和药理学方法增强HIF-1α信号转导 评估RGC代谢偏向厌氧糖酵解是否会使RGC产生耐药性 线粒体功能障碍，可能是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