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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

基本信息

批准号：
9371803
负责人：
Patrick Shih
金额：
$ 9万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9371803
关键词：
Address Advisory Committees Affect Anabolism Award Biochemical Biological Biological Availability Biological Process Biological Sciences Biology Brassica Broccoli - dietary Carbon Collaborations Communities 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 Institutes Institution Interdisciplinary Study Intestines Joints Laboratories Learning Link Malignant Neoplasms Mass Spectrum Analysis Measures Mentors Mentorship Metabolic Metabolic Pathway Metabolism Methods Molecular Mus Natural Products Nicotiana Nutritional Organism Pathway interactions 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 biosynthetic product 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 novel nutrition pathogen plant growth/development programs research and development screening small molecule stem synthetic biology tool tool development trait visiting scholar

项目摘要

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.

项目概要和摘要候选人与环境在加州大学伯克利分校的研究生生涯中，我对代谢的进化和工程产生了兴趣，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，并将其融入我的研究生工作，通过工程合成碳固定途径，以提高光合作用产量和生物遗传学预测的存在了数亿年的酶的合成前我对植物合成生物学的前景感到兴奋，博士后奖学金，并加入多米尼克Loqué博士在联合生物能源研究所和劳伦斯伯克利的实验室国家实验室，在那里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。虽然我的博士后生涯主要集中在工具开发上，但我对这些技术将设计具有独特生物功能的新型天然产物生物合成途径。我的长- 长期职业目标涉及合成生物学工具和平台的开发，以实现基本的发现和涉及植物天然产物和代谢工程的转化研究。我多样化的研究经验为实现这一目标奠定了坚实的基础。虽然我职业生涯的大部分时间都在关注初级碳代谢和光合作用，我还没有受过任何训练，在次生代谢和阐明自然产物生物合成途径。因此，我的近期目标是获得K99/R 00奖下的培训，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物的兴趣，最终转为独立教师职位。我的指导团队由不同但互补的领域的专家组成，使我能够接受培训在各自的利基和有机地建立自己的独立研究计划。我将由博士共同指导。 Dominique Loqué（劳伦斯伯克利国家实验室/加州大学伯克利分校），植物合成生物学专家，伊丽莎白博士 Sattely（斯坦福大学），植物次生代谢的领先专家，和Jay Keasling博士（劳伦斯伯克利国家实验室/加州大学伯克利分校），微生物合成生物学和代谢工程的先驱。我将接受进一步的培训， Justin Sonnenburg博士（斯坦福大学）作为合作者和研究小分子在生物学中作用的专家，肠道微生物群我将定期与我的咨询委员会进行一对一的会议，以确保我走上正轨随着我的职业发展和研究进展，获得了独立的教师职位。伯克利和斯坦福大学之间的邻近将使我能够利用优秀的学术优势。两个机构的环境，提供机会，以满足访问学者，参加研讨会，并采取从课程该领域的专家。此外，合成生物学和植物生物学领域的领先专家都是这两个组织的成员。大学，提供机会，从其他杰出的教师接受指导和研究投入。我带两所学校都提供有关职业和专业发展的研讨会和工作坊。相结合伯克利和斯坦福大学之间的导师和专业培训将提供建立我的职业生涯所需的培训。拥有独特的跨学科研究计划，融合了合成生物学和植物次生代谢。研究植物产生丰富的天然产物，对人类的营养、疾病和整体幸福然而，由于许多这些专门的代谢物的复杂性，我们在我们的研究中受到限制。研究单个植物化学物质对人类健康影响的能力。最近，新兴的合成生物学领域提供了将生物系统分解为单个组成部分的方法，使科学家能够逆转设计并重建它们的生化组成。这种方法在很大程度上仅限于简单的生物体（例如，E. 大肠杆菌和酵母）;然而，植物提供了一个独特的平台来利用合成生物学。我的研究主要集中在引入设计和工程学原理，合理调控植物代谢，植物天然产物的生物合成和生理作用。可食用十字花科植物（例如，西兰花、小白菜）由于吲哚芥子油苷衍生物的多样性，它们与癌症预防有关。然而，在这方面，由于十字花科植物中产生的生物活性化合物的多样性，精确定位可能负责癌症预防这样复杂特性的特定分子。结果很多研究结果相互矛盾，硫代葡萄糖苷与其声称的营养成分之间的联系也很薄弱。效益将特异性靶分子工程化到没有基础生物活性的新宿主中可以提供洞察力，有助于在分子水平上阐明它们在人类健康中的作用。植物合成生物学平台的发展，生产和提供特定浓度的目标植物天然产物将使未来的研究，定量研究硫代葡萄糖苷对人体健康的益处和影响。