Microbial Synthesis of Therapeutic Bile Acids

治疗性胆汁酸的微生物合成

• 批准号: 10010076
• 负责人: DEZHI LIAO
• 金额: $ 45.02万
• 依托单位: METSELEX, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010076
• 关键词: APP-PS1; Abate; Acute; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid beta-Protein; Anabolism; Animals; Apoptosis Inhibitor; Apoptotic; Artemia; Bacteria; Bile Acids; Bioinformatics; Biological; Businesses; Cause of Death; Cell Death; Cells; Chemicals; Chenodeoxycholic Acid; Cholesterol; Cholic Acids; Chronic; Clinical Trials; Complex; Cytoplasm; DNA; DNA biosynthesis; Deletion Mutation; Dendritic Spines; Development; Disease; Dose; Drug Kinetics; Economic Burden; Endoplasmic Reticulum; Engineering; Enzymes; Equilibrium; Ergosterol; Experimental Designs; Fermentation; Functional disorder; Gallbladder; Gene Expression; Genes; Genetic; Goals; Grant; Harvest; Hippocampus (Brain); Human; Industrialization; Industry; Learning; Measures; Membrane Lipids; Memory impairment; Metabolic; Metabolic Pathway; Minnesota; Mitochondria; Morphology; Mutation; NADH; NADP; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Organism; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Signal Sequences; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Procedures; Process; Production; Productivity; Property; Proteins; Reaction; Reactive Oxygen Species; Recombinants; Research; Role; Route; Saccharomyces cerevisiae; Small Business Technology Transfer Research; Societies; Source; Stretching; Synapses; Techniques; Technology; Technology Transfer; Therapeutic; Toxic effect; Treatment Cost; Universities; Ursidae Family; Ursodeoxycholic Acid; Vertebral column; Work; Yeasts; abeta oligomer; amyloid precursor protein processing; analog; analytical method; base; care costs; combat; cost estimate; design; design and construction; disability; drug development; endoplasmic reticulum stress; experience; frontal lobe; gene discovery; gene product; gut microbiome; improved; in vitro Assay; large scale production; microbial; microbial host; mouse model; mutant; novel therapeutics; peroxisome; prevent; reconstitution; reconstruction; response; scaffold; screening; stoichiometry; success; tauroursodeoxycholic acid; tool

ABSTRACT This Phase STTR Phase I proposal aims to engineer a synthetic metabolic pathway in a microbial host to produce UDCA and related compounds. The proposed work has high intellectual merit for the following reasons: (i) UDCA biosynthesis does not occur in any organism whose cultivation can be scaled to meet global demand, (ii) UDCA requires a multi-organism biosynthetic pathway (animal cholic acids converted to UDCA by the gut microbiome) that will have to be reconstituted in a single cell, and (iii) the anticipated scale and complexity of this engineering effort (combining more than a dozen genes from four organisms) are on the edge of what is feasible. Technical hurdles involve the discovery of new enzymes that convert ergosterol to cholesterol (a process known to exist in brine shrimp), achieving proper localization and enzymatic activity for fifteen recombinant gene products in yeast, and balancing the expression levels of each gene to support high-titer production of UDCA in yeast. The combined Metselex/University of Minnesota team will overcome these hurdles using their platform for multi-gene pathway refactoring and high-throughput DNA assembly and analytical methods. Experience with these tools/approaches and success in engineering similar synthetic metabolic pathways qualifies this team conduct these studies and will enable them to accomplish their Phase I goals.

摘要 这项STTRI阶段计划的目标是在微生物宿主中设计一条合成代谢途径，以产生 UDCA及相关化合物。拟议的工作具有很高的智力价值，原因如下：(I)UDCA 生物合成不会发生在任何可以规模化培养以满足全球需求的有机体中，(Ii)UDCA 需要多种生物的生物合成途径(肠道微生物将动物胆酸转化为UDCA) 这将不得不在单个细胞中重组，以及(Iii)这项工程的预期规模和复杂性 这一努力(结合了来自四个生物体的十几个基因)几乎是可行的。技术 障碍包括发现将麦角固醇转化为胆固醇的新酶(已知存在于 卤虾)，实现了15个重组基因产物在酵母中的适当定位和酶活性， 平衡每个基因的表达水平，以支持酵母中UDCA的高效生产。这个 Metselex/明尼苏达大学联合团队将利用他们的多基因平台克服这些障碍 途径重构和高通量DNA组装与分析方法。使用这些工具的经验 工具/方法和在设计类似合成代谢途径方面的成功使该团队的行为合格 这些研究将使他们能够实现第一阶段的目标。

项目成果

The Accumulation of Tau in Postsynaptic Structures: A Common Feature in Multiple Neurodegenerative Diseases?

• DOI: 10.1177/1073858420916696
• 发表时间: 2020-10
• 期刊: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
• 作者: Teravskis PJ;Ashe KH;Liao D
• 通讯作者: Liao D