Developing plant synthetic biology platforms to elucidate the role of natural products

开发植物合成生物学平台以阐明天然产物的作用

• 批准号: 9769625
• 负责人: Patrick Shih
• 金额: $ 23.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769625
• 关键词: Address; Advisory Committees; Affect; Anabolism; Antineoplastic Agents; Award; Biochemical; Biological; Biological Availability; Biological Process; Biological Sciences; Biology; Brassica; Broccoli - dietary; Carbon; Collaborations; Complex; Complex Mixtures; Conflict (Psychology); Consumption; Development; Diet; Disease; Edible Plants; Educational workshop; Engineering; Ensure; Environment; Enzymes; Escherichia coli; Evolution; Faculty; Family; Fellowship; Foundations; Future; Generations; Glucosinolates; Goals; Health; Health Benefit; Human; Hydrolysis; Individual; Indole Alkaloids; Indoles; Ingestion; Institutes; Institution; Interdisciplinary Study; Intestines; Joints; Laboratories; Learning; Link; Mass Spectrum Analysis; Measures; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Methods; Molecular; Mus; Natural Products; Nicotiana; Nutritional; Organism; Pathway interactions; Personal Satisfaction; Pharmacologic Substance; Photosynthesis; Phylogenetic Analysis; Physiological; Phytochemical; Plant Components; Plant Sources; Plants; Play; Positioning Attribute; Process; Production; Property; Research; Rice; Role; Schools; Scientist; Sulfur; System; Techniques; Technology; Time; Tobacco; Training; Transgenic Organisms; Translational Research; Universities; Vegetables; Work; Yeasts; antimicrobial; antimicrobial drug; base; biological systems; cancer prevention; carbon fixation; career; career development; design; design and construction; experience; experimental study; feeding; gut microbiome; gut microbiota; improved; insight; interest; meetings; member; metabolic engineering; microbial; microbial community; microbiome composition; novel; nutrition; pathogen; plant growth/development; programs; research and development; screening; small molecule; stem; synthetic biology; tool; tool development; trait; visiting scholar

Project Summary and Abstract Candidate and Environment During my graduate career at UC Berkeley, I became interested in the evolution and engineering of metabolic pathways, primarily relating to photosynthesis. It was through this work that I became familiar with the field of synthetic biology and integrated it into my graduate work through engineering synthetic carbon fixation pathways to improve photosynthetic yield and the synthesis of phylogenetically predicted enzymes that existed hundreds of millions of years ago. Excited about the prospects of synthetic biology in plants, I received a Life Sciences Research Foundation postdoctoral fellowship and joined Dr. Dominique Loqué's lab at the Joint BioEnergy Institute and Lawrence Berkeley National Laboratory, where I have focused on developing plant synthetic biology tools to facilitate metabolic engineering in plants. Although I have spent my postdoctoral career focused on tool development, I am interested in the application of these technologies to engineer novel natural product biosynthetic pathways with unique biological functions. My long- term career goals involve the development of synthetic biology tools and platforms for enabling basic discovery and translational research involving plant natural products and metabolic engineering. My diverse research experiences provide a strong foundation to attain this goal. Although I have spent much of my career focusing on primary carbon metabolism and photosynthesis, I have not yet had any training in secondary metabolism and elucidation of natural product biosynthetic pathways. Thus, my immediate goal is to obtain training from the K99/R00 award under the guidance of experts in the field to successfully bridge my interests in synthetic biology and plant natural products and ultimately transition to an independent faculty position. My mentoring team is composed of experts in disparate yet complementary fields, allowing me to receive training in their respective niches and organically build my own independent research program. I will be co-mentored by Dr. Dominique Loqué (Lawrence Berkeley National Lab/UC Berkeley), an expert in plant synthetic biology, Dr. Elizabeth Sattely (Stanford), a leading expert in plant secondary metabolism, and Dr. Jay Keasling (Lawrence Berkeley National Lab/UC Berkeley), a pioneer in microbial synthetic biology and metabolic engineering. I will receive further training and guidance form Dr. Justin Sonnenburg (Stanford) as a collaborator and expert studying the role of small molecules on the intestinal microbiota. I will have regular one-on-one meetings with my advisory committee to ensure that I stay on track with my career development and research progress to obtain an independent faculty position. The proximity between both Berkeley and Stanford will enable me to take advantage of the excellent academic environment of both institutions, providing opportunities to meet visiting scholars, attend seminars, and take courses from experts in the field. Furthermore, leading experts in the field of synthetic biology and plant biology are members of both universities, providing opportunities to receive guidance and input on research from other distinguished faculty. I will take advantage of seminars and workshops on career and professional development offered by both schools. The combination of mentorship and professional training between Berkeley and Stanford will provide the training needed to establish my own unique interdisciplinary research program merging synthetic biology and plant secondary metabolism. Research Plants produce a wealth of natural products that have wide-ranging effects on human nutrition, disease, and overall wellbeing. However, because of the complexities of many of these specialized metabolites, we have been limited in our ability to study the effects of individual phytochemicals on human health. Recently, the nascent field of synthetic biology has provided the means to dissect biological systems into their individual components, enabling scientists to reverse engineer and reconstruct their biochemical makeup. This approach has largely been limited to simple organisms (e.g., E. coli and yeast); however, plants provide a unique platform to leverage synthetic biology. My research focuses on introducing design and engineering principles to rationally manipulate plant metabolism in order to investigate the biosynthesis and physiological roles of plant natural products. Edible cruciferous plants (e.g., broccoli, bok choy) have been implicated in cancer prevention, stemming from their diversity of indole glucosinolate derivatives. However, because of the vast diversity of bioactive compounds produced in cruciferous plants, it is challenging to tease apart and pinpoint the specific molecules that may be responsible for a trait as complex as cancer prevention. As a result, many studies have resulted in conflicting findings and tenuous links between glucosinolates and their claimed nutritional benefits. Engineering specific target molecules into novel hosts with no basal biological activity may provide insight and help clarify their role in human health at a molecular level. The development of plant synthetic biology platforms to produce and deliver specific concentrations of target plant natural products will enable future studies to more quantitatively study the claimed benefits and effects of glucosinolates on human health.

项目摘要和摘要 候选人和环境 在加州大学伯克利分校的研究生生涯中，我对代谢的发展和工程感兴趣 途径，主要与光合作用有关。正是通过这项工作，我熟悉了合成领域 生物学并通过工程合成碳固定途径将其整合到我的研究生工作中以改进 光合产量和合成的系统发育预测的酶，这些酶存在数亿年 前。对植物中合成生物学的前景感到兴奋，我收到了生命科学研究基金会 博士后奖学金，并在联合生物能源研究所和劳伦斯·伯克利（Lawrence Berkeley）的DominiqueLoqué博士实验室加入 国家实验室，我专注于开发植物合成生物学工具，以促进代谢工程 在植物中。尽管我将博士后职业集中在工具开发上，但我对应用 这些技术能够通过独特的生物学功能来设计新型的天然产物生物合成途径。我的长期 职业生涯目标涉及合成生物学工具和平台的开发，以实现基本发现和 转化研究涉及植物天然产品和代谢工程。我多样化的研究经验 为实现这一目标提供了坚实的基础。尽管我的职业生涯大部分时间都集中在主要碳 代谢和光合作用，我尚未接受过次要代谢和自然阐明的任何培训 产品生物合成途径。那是我的近期目标是从K99/R00奖中获得培训 该领域专家的指导成功地弥合了我对合成生物学和植物天然产品的兴趣以及 最终过渡到独立教师职位。 我的心理团队由不同但完整领域的专家组成，使我可以接受培训 在各自的利基市场中，有机地构建了我自己的独立研究计划。我将由博士授予。 DominiqueLoqué（Lawrence Berkeley National Lab/UC Berkeley），植物合成生物学专家，伊丽莎白博士 Sattely（Stanford），植物次要代谢的主要专家和Jay Keasling博士（劳伦斯·伯克利国家 Lab/UC Berkeley），微生物合成生物学和代谢工程的先驱。我将获得进一步的培训， 贾斯汀·索南堡（Justin Sonnenburg）博士（斯坦福大学）的指导形式，是研究小分子在 肠菌群。我将与咨询委员会定期进行一对一的会议，以确保我保持正轨 随着我的职业发展和研究进展，以获得独立的教师职位。 伯克利和斯坦福大学之间的距离将使我能够利用优秀的学术 这两个机构的环境，提供机会与访问学者见面，参加半手赛并参加课程 该领域的专家。此外，合成生物学和植物生物学领域的主要专家都是两者的成员 大学提供了获得其他杰出教师的研究指导和投入的机会。我会接受的 两所学校提供的关于职业和专业发展的精神诊所和讲习班的优势。组合 伯克利和斯坦福大学之间的精神训练和专业培训将提供建立我的培训 拥有独特的跨学科研究计划，融合了合成生物学和植物次要代谢。 研究 植物生产大量天然产品，这些产品对人类营养，疾病和整体产生广泛影响 福利。但是，由于许多这些专业代谢物的复杂性，我们在我们的 能够研究单个生理学对人类健康的影响。最近，合成生物学的新生领域 已经提供了将生物系统剖析到其各个组件中的方法，使科学家能够逆转 工程和重建其生化构成。这种方法在很大程度上仅限于简单的生物（例如，E。 大肠杆菌和酵母）；但是，植物提供了一个独特的平台来利用合成生物学。我的研究重点 引入设计和工程原则以合理操纵植物代谢，以调查 植物天然产品的生物合成和物理作用。可食用的十字花科植物（例如西兰花，Bok Choy）具有 由于它们的吲哚葡萄糖苷衍生物的多样性，暗示了癌症预防。然而， 由于十字花科植物中产生的生物活性化合物的大量多样性，取笑和 查明可能导致与预防癌症一样复杂的特定分子。结果，许多 研究导致发现矛盾的发现和葡萄糖醇之间的微弱联系及其所声称的营养 好处。没有基本生物学活动的新型宿主的工程特定靶标分子可能会提供洞察力，并且 帮助阐明他们在分子水平上在人类健康中的作用。植物合成生物学平台的发展 生产并提供特定浓度的目标植物天然产品将使以后的研究能够增加 定量研究葡萄糖剂对人类健康的益处和影响。