Metabolic Reprogramming for Photoreceptor Neuroprotection

光感受器神经保护的代谢重编程

• 批准号: 10200068
• 负责人: Cagri Besirli
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200068
• 关键词: Acute; Address; Aerobic; Amino Acids; Anabolism; Apoptosis; Apoptosis Regulation Gene; Apoptotic; Autophagocytosis; Bioenergetics; Blindness; Budgets; Cell Death; Cell Survival; Cessation of life; Disease; Energy Metabolism; Enzymes; Equilibrium; Foundations; Future; Gatekeeping; Generations; Genetic; Glycolysis; Goals; Hexokinase 2; Homeostasis; Inherited; Intervention; Knockout Mice; Knowledge; Link; Lipids; Macular degeneration; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modality; Modeling; Molecular; Mus; Muscle; Neuroprotective Agents; Nucleotides; Nutrient; Patients; Pharmacology; Photoreceptors; Protein Isoforms; Proto-Oncogene Proteins c-akt; Public Health; Pyruvate Kinase; Recombinant adeno-associated virus (rAAV); Regulation; Research; Retina; Retinal Cone; Retinal Detachment; Retinal Diseases; Rod; Role; Signal Transduction; Stress; Testing; Therapeutic; aerobic glycolysis; base; detection of nutrient; improved; inhibitor/antagonist; innovation; neuroprotection; neurotrophic factor; novel; novel strategies; nutrient deprivation; overexpression; prevent; response; retinal apoptosis; retinal rods; sight restoration; treatment strategy; visual process

PROJECT SUMMARY A key gap remains in our ability to develop successful treatment strategies to prevent photoreceptor (PR) loss and restore vision. To address this gap, we are proposing novel strategies to reprogram metabolism and boost PR survival. PRs have unique metabolic adaptations and utilize aerobic glycolysis to budget their metabolic needs based on nutrient availability, balancing the synthesis of amino acid, nucleotide and lipid precursors with energy generation. PRs perform aerobic glycolysis by expressing hexokinase 2 (HK2) and pyruvate kinase muscle 2 (PKM2). HK2, the first enzyme of glycolysis, acts as an intracellular rheostat, a unique non-enzymatic function that links metabolic status to survival by regulating apoptosis and autophagy. PKM2 is the gatekeeper of energy metabolism and controls aerobic glycolytic flux. HK2 expression is critical for the survival of PRs, as replacing HK2 with HK1 isoform increases apoptosis after stress. Furthermore, replacing low-activity PKM2 with its high-activity isoform PKM1 increases total PKM activity in PRs and boosts survival after nutrient deprivation. The over-arching hypothesis of this proposal is that metabolic reprogramming of PRs, by modulating HKs and PKMs, will enhance survival of stressed PRs, enzymatically by increasing energy generation via glycolysis, and non-enzymatically by inhibiting death signals during energy crisis. The objectives in this project are to: 1) utilize genetic and pharmacologic manipulation of PKM and HK function and prevent retinal detachment induced PR death by metabolic reprograming; and 2) identify non- enzymatic functions of HKs that regulate PR survival during experimental retinal detachment. Aim 1: To test the hypothesis that augmenting energy homeostasis by altering PKM function will enhance PR survival during stress. Our hypothesis predicts that increasing total PKM activity provides survival advantage during apoptotic stress by shifting PR metabolism to more efficiently generate ATP from limited energy substrates. These studies will measure glycolytic flux, ATP generation, and cell death in an acute PR stress model upon Pkm1 overexpression or pharmacologic activation of PKM2. Aim 2: To test the hypothesis that HK2 is the molecular rheostat that links metabolic status to PR apoptosis and autophagy. Our hypothesis predicts that HK2 links PR metabolic needs to survival and that HK2 to HK1 reprograming will decouple metabolic regulation of apoptosis and autophagy. These studies will identify the links between HK2 and key regulators of apoptosis and autophagy in PRs and will measure the effect of HK2 to HK1 reprogramming on glycolysis, biosynthesis, and PR cell death. Our approach is innovative as we will connect the unique energy metabolism of PRs directly to cell death regulation via manipulating the key mediators of aerobic glycolysis, i.e. PKM2 and HK2. The proposed research is significant in that it will provide critical information on how unique metabolic adaptations of PRs influence cell survival and lay the foundation for future studies exploring the connections between metabolism and PR survival in retinal diseases.

项目总结