Glutamine as an alternative fuel source for photoreceptors

概述：感光细胞死亡是许多视网膜疾病中视力丧失的最终原因， 对神经保护疗法的未满足的需求，以提高他们的生存率。生物能量需求 光感受器与肿瘤组织的光感受器相当。为了满足这种需求，光感受器具有独特的代谢能力， 适应预算他们的生物能量需求。其中一种适应是利用有氧糖酵解， 葡萄糖代谢是光感受器生理学研究的中心。即便如此，燃料以外的 葡萄糖可用于满足光感受器的需要，尤其是在生物能量应激期间。 考虑到它们拥挤，营养有限的环境，光感受器可能已经进化到去除任何刚性的 燃料来源的限制。这一建议将提供一个潜在的贡献的基本见解 光感受器代谢、功能和存活的替代燃料源，同时为 职业发展的关键技能。这项工作的长期目标是发展所需的技能， 作为一名独立的临床医生-科学家，研究预防光感受器变性导致视力丧失的新疗法。 本K 08提案的科学目的是检验谷氨酰胺是关键燃料的假设 维持光感受器生物量、调节氧化还原平衡和促进光感受器存活的来源 营养缺乏的时期。我们建议评估谷氨酰胺在体外和体内的代谢命运， 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 通过破坏光受体特异性谷氨酰胺酶（Gls）条件性敲除中的谷氨酰胺催化剂而存活 老鼠.两个集中的具体目标将被用来研究我们的假设：1）确定谷氨酰胺如何 有助于光感受器生物量的组成并调节氧化还原平衡。2)确定如何 光感受器利用谷氨酰胺作为替代燃料源以促进外部视网膜应激期间的存活。 职业发展目标是培养发展所需的技能和指导 在代谢组学数据的应用，获取和分析方面的专业知识，并实现科学的 独立课程，研讨会和导师将补充研究。多- 导师的纪律团队，每个人都有一个互补的技能，是深深致力于校长 调查员的成功密歇根大学眼科和视觉科学系 拥有世界一流的师资和设施，所提出的研究非常符合国际 在密歇根大学代谢和代谢组学方面的公认专业知识， 团队机构环境、指导和职业发展计划最大限度地提高了 研究目标和主要研究者成为独立临床科学家的能力 光感受器代谢和存活的界面，以开发新的治疗范例， 视网膜疾病中的视力丧失。

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.