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：
10677583
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/10677583
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 Institution International Knockout Mice Label Laboratories 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 Nutrient availability Ophthalmology Optical Coherence Tomography Oxidation-Reduction Oxidative Stress 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 Tissues Tracer Universities Work aerobic glycolysis career development clinical care conditional knockout deprivation experience glucose metabolism improved in vivo inherited retinal degeneration insight knock-down metabolomics multidisciplinary neoplastic neuroprotection 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残留障碍中视力丧失的最终原因，并且有对神经保护疗法的不满，以提高其生存率。生物能的要求光感受器的色带是肿瘤组织的。为了满足这种需求，感光体具有独特的代谢适应预算其生物能量需求。一种这样的适应是有氧糖酵解的利用，因此葡萄糖代谢在光感受器生理的研究中一直是核心。即便如此，除了葡萄糖可用于满足感光体的需求，尤其是在生物能胁迫时期。鉴于它们拥挤的营养限制环境，感光体可能已经演变为去除任何刚性燃料来源的限制。该提案将提供对潜在贡献的基本见解光感受器代谢，功能和生存的替代燃料来源，同时为基板提供职业发展的重要技能。这项工作的长期目标是发展追求所需的技能。可防止光感受器变性视力丧失的新型疗法作为独立的临床科学家。该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增强光感受器存活的来源营养剥夺时期。我们建议在体外和体内评估谷氨酰胺的代谢命运稳定的异位代谢通量分析及其对感光器氧化还原平衡，功能和功能的贡献通过破坏光感受器特异性谷氨酰胺酶（GLS）条件敲除中的谷氨酰胺分解代谢来生存老鼠。将利用两个重点的特定目标来研究我们的假设：1）确定谷氨酰胺如何有助于感光生物量的成分，并调节氧化还原稳态。 2）确定如何感光体利用谷氨酰胺作为替代燃料来源来促进外部永久应力期间的生存。职业发展目标是培养发展所需的技能和精神训练对代谢组学数据的应用，获取和分析的专业知识，并获得科学独立。课程，半手和精神训练将完成研究。多纪律导师团队，每个人都具有完善的技能，致力于校长调查员的成功。眼科与视觉科学系和密歇根大学拥有世界一流的教职员工和设施，该研究提出的提议与国际非常适合在密歇根大学和心理中的代谢和代谢组学方面的认可专业知识团队。机构环境，心理和职业发展计划最大化研究目的以及主要研究者成为独立临床科学家研究的能力光感受器代谢和生存的界面，以发展新的热范式永久疾病的视力丧失。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retinal Detachment After Endophthalmitis: Risk Factors and Outcomes.

DOI：
10.2147/opth.s302757
发表时间：
2021
期刊：
Clinical ophthalmology (Auckland, N.Z.)
影响因子：
0
作者：
Wang T;Moinuddin O;Abuzaitoun R;Hwang M;Besirli C;Wubben TJ;Zacks DN
通讯作者：
Zacks DN

Contemporary Management of Complex and Non-Complex Rhegmatogenous Retinal Detachment Due to Giant Retinal Tears.

DOI：
10.2147/opth.s299762
发表时间：
2021
期刊：
Clinical ophthalmology (Auckland, N.Z.)
影响因子：
0
作者：
Li KX;Carducci N;Moinuddin O;Zhou Y;Musch DC;Zacks DN;Besirli CG;Wubben TJ
通讯作者：
Wubben TJ

Photoreceptor metabolic reprogramming: current understanding and therapeutic implications.

DOI：
10.1038/s42003-021-01765-3
发表时间：
2021-02-24
期刊：
Communications biology
影响因子：
5.9
作者：
Pan WW;Wubben TJ;Besirli CG
通讯作者：
Besirli CG

Surgical repair of primary non-complex rhegmatogenous retinal detachment in the modern era of small-gauge vitrectomy.

DOI：
10.1136/bmjophth-2020-000651
发表时间：
2021
期刊：
BMJ open ophthalmology
影响因子：
2.4
作者：
Moinuddin O;Abuzaitoun RO;Hwang MW;Sathrasala SK;Chen XD;Stein JD;Johnson MW;Zacks DN;Wubben TJ;Besirli CG
通讯作者：
Besirli CG

Cost Analysis of Intravitreal Aflibercept vs Vitrectomy With Panretinal Photocoagulation for Vitreous Hemorrhage From Proliferative Diabetic Retinopathy.

玻璃体内阿柏西普与全视网膜光凝玻璃体切除术治疗增殖性糖尿病视网膜病变玻璃体出血的成本分析。