Metabolism during the Progression of Photoreceptor Degeneration

感光器退化过程中的代谢

• 批准号: 10638849
• 负责人: Daniel T Hass
• 金额: $ 11.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638849
• 关键词: Affect; Age; Blindness; Bypass; Carbon; Carotid Arteries; Catheters; Choroid; Circulation; Citric Acid Cycle; Compensation; Consumption; Cysteine; Cytolysis; Data; Development; Disease; Educational workshop; Electroretinography; Energy Metabolism; Eye; Fatty Acids; Genes; Genetic Diseases; Gluconeogenesis; Glucose; Glutamine; Glycogen; Glycolysis; Goals; Health; Impairment; Infusion procedures; Inherited; Label; Laboratories; Learning; Leucine; Light; Lipids; Malates; Measures; Mediating; Mentors; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Mutation; Nature; Operative Surgical Procedures; Optical Coherence Tomography; Palmitates; Palmitic Acids; Pathway interactions; Patients; Pentose Phosphate Cycle Pathway; Pentosephosphate Pathway; Phenotype; Photoreceptors; Physiological; Positioning Attribute; Process; Proline; Pyruvate; Research; Research Personnel; Retina; Retinitis Pigmentosa; Scientist; Source; Stains; Structure of jugular vein; Structure of retinal pigment epithelium; Testing; Thick; Tissues; Training; Work; aerobic glycolysis; beta-Hydroxybutyrate; career development; early onset; experimental study; glucose transport; improved; in vivo; individualized medicine; meter; mouse model; photoreceptor degeneration; preservation; prevent; programs; promote resilience; protein expression; response; skills; symposium; therapeutic development

Project Summary/Abstract Retinitis pigmentosa (RP) is an inherited, early-onset, and irreversible form of vision loss. RP can result from mutations in over 100 unique genes. The burden of developing individualized treatments for each mutation is high, so strategies that improve photoreceptor health regardless of mutation would be benefit patients. RP perturbs retina energy metabolism, and disrupted energy metabolism can cause degeneration. Metabolic reprogramming may prevent photoreceptor loss. Reprogramming efforts should be aimed at correcting changes that occur with RP, yet it is unclear which changes to correct. In RP there are disruptions in glucose transport, aerobic glycolysis and the normal expression of TCA cycle and pentose phosphate pathway (PPP) genes. Due to critical gaps in these studies, the nature and timing of these changes is unclear. The lack of comprehensive detail on how RP alters metabolic flux hampers efforts to protect photoreceptors. The aims of this application are aimed at understanding changes to metabolism in RP. Specifically, in aim 1 I will determine how the rate of metabolism changes with disease stage. I will infuse 13C-labeled glucose or lactate through catheters to probe flux of carbons through metabolic pathways in the retina and RPE-choroid. I will quantify 13C accumulation in metabolites of glycolysis, the TCA cycle, the PPP, gluconeogenesis, and glycogen. Metabolites that fuel these pathways must first be transported from circulation, through the retinal pigment epithelium (RPE), and to the retina. In Aim 2 I will determine metabolites that increase O2 consumption by ex vivo RPE-choroid, and which of these best labels intermediates in the RPE-choroid in vivo. This proposal also seeks support for my career development. My development goals include presenting my work at conferences and leveraging these presentations to form a scientific network. I will also take scientific and non-scientific courses to improve my ability to perform surgeries and mentor young scientists. These opportunities will prepare me for a position as an independent investigator, where I can continue to fulfill the aims of this proposal and further develop my research program.

项目总结/摘要 视网膜色素变性（RP）是一种遗传性、早发性和不可逆的视力丧失形式。RP可能由以下原因导致 超过100个独特基因的突变为每种突变开发个体化治疗的负担是 因此，无论突变如何，改善感光细胞健康的策略都将使患者受益。 RP扰乱视网膜能量代谢，能量代谢紊乱可导致变性。代谢 重编程可以防止光感受器损失。重新编制方案的努力应旨在纠正 RP发生的变化，但尚不清楚哪些变化要纠正。在RP中， 葡萄糖转运、有氧糖酵解以及TCA循环和戊糖磷酸途径的正常表达 (PPP)基因.由于这些研究中存在关键空白，这些变化的性质和时间尚不清楚。缺乏 关于RP如何改变代谢通量阻碍保护光感受器的努力的全面细节。 本申请的目的是了解RP中代谢的变化。具体而言，在目标1 I中， 将决定代谢率如何随疾病阶段而变化。我会注入13 C标记的葡萄糖 通过导管测量乳酸盐，以探测通过视网膜和RPE-脉络膜中的代谢途径的碳通量。我 将量化糖酵解代谢物中的13 C积累，TCA循环，PPP，异生， 糖原为这些通路提供燃料的代谢物必须首先从循环系统通过视网膜转运， 色素上皮（RPE）和视网膜。在目标2中，我将确定增加O2的代谢物 通过离体RPE-脉络膜的消耗，以及这些最佳标记物中的哪一个在体内RPE-脉络膜中中间体。 这份提案也寻求对我职业发展的支持。我的发展目标包括展示我的 在会议上工作，并利用这些演示文稿形成一个科学网络。我也将采取科学的 和非科学课程，以提高我的能力，进行手术和指导年轻科学家。这些 机会将准备我作为一个独立的调查员的位置，在那里我可以继续履行 这一建议的目的，并进一步发展我的研究计划。