Glutamine as an alternative fuel source for photoreceptors

谷氨酰胺作为光感受器的替代燃料来源

基本信息

批准号：
10219272
负责人：
Thomas Joseph Wubben
金额：
$ 23.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10219272
关键词：
Acute Aerobic Age related macular degeneration Amino Acids Apoptosis Bioenergetics Biomass Blindness Budgets Carbon Caregivers Catabolism Cell Death Cell Line Cell Survival Cell physiology Cessation of life Citric Acid Cycle Complement Consumption Crowding Data Development Development Plans Disease Electroretinography Environment Enzymes Equilibrium Eye diseases Faculty Generations Genes Glucose Glutamates Glutaminase Glutamine Glutathione Goals Health Histology Homeostasis Hypoxia In Vitro International Knockout Mice Label Laboratories Life Link Lipids Maintenance Malignant Neoplasms Mentors Mentorship Metabolic Metabolism Methodology Michigan Modeling Mus NADP Nitrogen Nonexudative age-related macular degeneration Nucleic Acids Nucleotide Biosynthesis Nutrient Ophthalmology Optical Coherence Tomography Oxidation-Reduction Oxidative Stress Oxides Patients Photoreceptors Phototransduction Physiology Principal Investigator Process Production Professional Competence Pyruvate Quality of life Reactive Oxygen Species Research Research Personnel Research Proposals Resources Retina Retinal Detachment Retinal Diseases Role Scientist Secondary to Source Stress Testing Therapeutic Time Tissues Tracer Universities Work aerobic glycolysis base career development clinical care conditional knockout data resource deprivation experience glucose metabolism improved in vivo inherited retinal degeneration insight knock-down metabolomics multidisciplinary neoplastic novel therapeutics nutrient deprivation photoreceptor degeneration prevent productivity loss response retinal rods skills stable isotope success vision science

项目摘要

SUMMARY: Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective therapies to improve their survival. The bioenergetic requirements of photoreceptors rival that of neoplastic tissue. To meet this demand, photoreceptors have unique metabolic adaptations to budget their bioenergetic needs. One such adaptation is the utilization of aerobic glycolysis, so glucose metabolism has been central in the study of photoreceptor physiology. Even so, fuels other than glucose may be used to meet the needs of photoreceptors, especially during times of bioenergetic stress. Given their crowded, nutrient-limited environment, photoreceptors may have evolved to remove any rigid constraints on fuel sources. This proposal will provide fundamental insight into the contribution of a potential alternative fuel source to photoreceptor metabolism, function, and survival, while providing the substrate for critical skills in career development. The long-term goal of this work is to develop the skills needed to pursue novel therapies that prevent vision loss in photoreceptor degenerations as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that glutamine is a key fuel source to maintain photoreceptor biomass, regulate redox balance, and boost photoreceptor survival during periods of nutrient deprivation. We propose to assess the metabolic fate of glutamine in vitro and in vivo using stable-isotope metabolic flux analysis and its contribution to photoreceptor redox balance, function, and survival by disrupting glutamine catabolism in a photoreceptor-specific, glutaminase (Gls) conditional knockout mouse. Two focused specific aims will be utilized to investigate our hypothesis: 1) Determine how glutamine contributes to components of photoreceptor biomass and regulates redox homeostasis.; 2) Determine how photoreceptors utilize glutamine as an alternative fuel source to promote survival during outer retinal stress. The career development objective is to cultivate the skills and mentorship required to develop expertise in the application, acquisition, and analysis of metabolomics data, and to achieve scientific independence. The coursework, seminars, and mentorship will complement the research. The multi- disciplinary team of mentors, each with a complementary skill set, is deeply committed to the principal investigator’s success. The Department of Ophthalmology and Visual Sciences and the University of Michigan has world-class faculty and facilities, and the research proposed fits exceptionally well with the internationally recognized expertise in metabolism and metabolomics at the University of Michigan and within the mentoring team. The institutional environment, mentoring, and career development plan maximize the success of the research aims and the ability of the principal investigator to become an independent clinician-scientist studying the interface of photoreceptor metabolism and survival to develop novel therapeutic paradigms that prevent vision loss in retinal disorders.

摘要：感光细胞死亡是许多视网膜疾病中视力丧失的最终原因，并且存在为提高其生存率而对神经保护疗法的需求未得到满足。光感受器可与肿瘤组织相媲美，为了满足这一需求，光感受器具有独特的代谢功能。适应预算其生物能量需求的一种适应是利用有氧糖酵解，因此即便如此，葡萄糖代谢一直是光感受器生理学研究的核心。葡萄糖可用于满足光感受器的需求，特别是在生物能量应激期间。鉴于其拥挤、营养有限的环境，光感受器可能已经进化到可以去除任何僵硬的物质。该提案将为潜在的贡献提供基本见解。光感受器代谢、功能和生存的替代燃料来源，同时提供底物这项工作的长期目标是培养追求职业发展所需的技能。作为独立的临床医生科学家，预防光感受器退化引起的视力丧失的新疗法。 K08 提案的科学目标是检验谷氨酰胺是关键燃料的假设维持光感受器生物量、调节氧化还原平衡并提高光感受器存活率的来源我们建议使用体外和体内评估谷氨酰胺的代谢命运。稳定同位素代谢通量分析及其对光感受器氧化还原平衡、功能和光感受器的贡献通过破坏光感受器特异性谷氨酰胺酶 (Gls) 条件性敲除中的谷氨酰胺分解代谢来维持生存小鼠。将利用两个重点具体目标来研究我们的假设：1）确定谷氨酰胺如何发挥作用。有助于光感受器生物量的组成并调节氧化还原稳态。; 2) 确定如何光感受器利用谷氨酰胺作为替代燃料来源，以促进外视网膜应激期间的生存。职业发展目标是培养发展所需的技能和指导代谢组学数据的应用、获取和分析方面的专业知识，并实现科学课程作业、研讨会和指导将补充研究。纪律导师团队，每个人都有互补的技能，都坚定地致力于校长眼科和视觉科学系和密歇根大学的成功。拥有世界一流的师资和设施，所提出的研究与国际水平非常吻合密歇根大学代谢和代谢组学方面公认的专业知识以及指导范围团队的制度环境、指导和职业发展计划最大限度地提高了团队的成功。研究目标和主要研究者成为独立临床医生科学家研究的能力光感受器代谢和存活的界面，以开发新的治疗范例，以预防视网膜疾病导致视力丧失。