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

项目摘要和摘要 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 途径，主要与光合作用有关。正是通过这份工作，我熟悉了合成材料领域 生物学，并将其整合到我的毕业工作中，通过工程合成固碳途径来改进 存在数亿年的光合作用效率和系统发育预测的酶的合成 那是以前的事了。对植物合成生物学的前景感到兴奋，我获得了生命科学研究基金会 博士后奖学金，并加入了多米尼克·洛凯博士在联合生物能源研究所和劳伦斯·伯克利的S实验室 在国家实验室，我一直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一直专注于工具开发，但我对 这些技术设计出具有独特生物功能的新型天然产物生物合成途径。我的龙- 任期的职业目标包括开发合成生物学工具和平台，以实现基本发现和 涉及植物天然产物和代谢工程的转化研究。我不同的研究经历 为实现这一目标提供坚实的基础。尽管我职业生涯的大部分时间都在关注初级碳 新陈代谢和光合作用，我还没有接受过任何关于次生代谢和阐明自然的训练 产物生物合成途径。因此，我的近期目标是获得K99/R00奖的培训 在该领域专家的指导下，成功地弥合了我对合成生物学和植物天然产品的兴趣 最终过渡到独立的教职员工职位。 我的指导团队由互不相同但又相互补充的领域的专家组成，使我能够接受培训 在各自的利基领域，有机地建立起自己的独立研究计划。我将由Dr。 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(Stanford)，领先的植物次生代谢专家，Jay Keasling博士(Lawrence Berkeley National) 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，并 来自Justin Sonnenburg博士(斯坦福)的指导，作为研究小分子在分子中的作用的合作者和专家 肠道微生物区系。我将定期与我的顾问委员会进行一对一的会议，以确保我保持在正轨上 随着我事业的发展和研究的进步，获得了一份独立的教职。 伯克利和斯坦福的距离很近，这将使我能够利用优秀的学术 两个机构的环境，提供机会会见访问学者，参加研讨会，并参加 该领域的专家。此外，合成生物学和植物生物学领域的顶尖专家都是这两个组织的成员 大学，提供机会接受其他杰出教员对研究的指导和投入。我要买下 利用两所学校举办的关于职业和专业发展的研讨会和工作坊。组合在一起 伯克利和斯坦福之间的指导和专业培训将提供所需的培训，以建立我的 自己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、疾病和整体都有广泛的影响 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 研究个别植物化学物质对人类健康的影响的能力。最近，合成生物学这一新兴领域 提供了将生物系统分解为各自组成部分的方法，使科学家能够逆转 设计并重建他们的生化组成。这种方法在很大程度上局限于简单的生物体(例如，E。 大肠杆菌和酵母)；然而，植物为利用合成生物学提供了一个独特的平台。我的研究重点是 介绍合理操作植物新陈代谢的设计和工程原理，以研究 植物天然产物的生物合成和生理作用。可食用的十字花科植物(如西兰花、白菜) 由于其吲哚硫代葡萄糖苷衍生物的多样性，被认为与癌症预防有关。然而， 由于十字花科植物中产生的生物活性化合物种类繁多，要将它们分离出来是一件具有挑战性的事情。 找出可能对癌症预防这样复杂的特征负责的特定分子。因此，许多人 研究发现硫代葡萄糖苷与其声称的营养成分之间存在相互矛盾的联系。 福利。将特定的靶分子工程到没有基本生物活性的新宿主中可能提供洞察力和 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开发 生产和交付特定浓度的目标植物天然产物将使未来的研究能够获得更多 定量研究硫代葡萄糖酸盐声称的益处和对人类健康的影响。

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.