Marine symbiotic interactions for discovery of bioactive compounds

海洋共生相互作用发现生物活性化合物

• 批准号: 8906200
• 负责人: Eric W Schmidt
• 金额: $ 5.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906200
• 关键词: Action Potentials; Affect; Anabolism; Animals; Anti-Bacterial Agents; Antibiotics; Automobile Driving; Bacteria; Bacterial Infections; Basic Science; Biological; Biological Assay; Biological Factors; Biology; Carbon; Cells; Chemicals; Chemistry; Development; Disease; Environment; Eukaryotic Cell; Evolution; FDA approved; Funding; Goals; Ion Channel; Lead; Libraries; Malignant Neoplasms; Marine Invertebrates; Marines; Methods; Microbe; Miniaturization; Molecular Target; Natural Products Chemistry; Neurologic; Neurology; New Agents; Organism; Pharmaceutical Preparations; Pharmacologic Substance; Principal Component Analysis; Research Personnel; Running; Shapes; Skeleton; Source; Symbiosis; System; Testing; Therapeutic Agents; Time; Universities; Utah; Wisconsin; base; coastal water; design; drug development; drug discovery; human disease; improved; innovation; metabolomics; microbial; nervous system disorder; novel strategies; oncology; programs; public health relevance; receptor; research study; scaffold; small molecule; working group

DESCRIPTION (provided by applicant): Virtually every animal on Earth interacts with bacteria. In many cases, over the course of ancient symbioses bacteria have evolved specific small molecule natural products to interact with their host organisms and with other competing microbes. These compounds can be exceptionally bioactive, and some are even FDA-approved agents for treating diseases such as cancers. The molecules presumably co-evolved with their molecular targets in many different animals, meaning that they are selected by evolution to have functional effects on animals. In turn, these effects can be exploited for the creation of new pharmaceuticals. These interactions are just beginning to be understood and represent a virtually untapped reservoir for discovering agents with potential to treat human diseases. Here, we will perform fundamental experiments on marine symbiotic systems, cultivate bacteria, and discover and develop bioactive small molecules. Our focus will be on molecules that affect competing bacteria (antibiotics) and the host organism (molecules that affect eukaryotic cells and might have use in neurology or oncology). We will take a rational, hypothesis-driven approach to understanding and exploiting symbiotic interactions. In this proposal, we will focus on associations between animals and bacteria in US coastal waters. There, we have found specific symbiotic bacteria that synthesize unexpectedly diverse new, bioactive compounds. We seek to understand these interactions while obtaining new compounds for further development as therapeutic agents. Our aims are to: 1) Understand how natural products shape symbiotic interactions. We will focus on specific interactions between different phyla of marine invertebrates and their associated, cultivable bacteria. 2) Discover new natural products from cultivated bacteria. We will use a metabolomics approach to rapidly hone in on previously unknown natural products. These compounds have been proven so far to be exceptionally active and include new compounds with new carbon skeletons. We will focus on innovative antibiotic and neuroactivity assays available at University of Wisconsin and University of Utah. We will also develop libraries that can be more widely screened. 3) Develop natural products for application in treating human diseases. We will combine chemical and biotechnological approaches to assess the promise of newly discovered agents and to move them toward application. We will begin with a few lead compounds already discovered in our labs, then use the established pipeline for other agents discovered in this project.

描述（由申请人提供）：几乎地球上的每一种动物都与细菌相互作用。在许多情况下，在古老的共生过程中，细菌已经进化出特定的小分子天然产物，与它们的宿主生物和其他竞争微生物相互作用。这些化合物可能具有异常的生物活性，有些甚至是FDA批准的用于治疗癌症等疾病的药物。这些分子可能与它们在许多不同动物中的分子靶点共同进化，这意味着它们被进化选择对动物产生功能性影响。反过来，这些效应可以用于创造新的药物。这些相互作用才刚刚开始被理解，并代表了一个几乎未开发的水库，用于发现有潜力治疗人类疾病的药物。在这里，我们将进行海洋共生系统的基础实验，培养细菌，发现和开发生物活性小分子。我们的重点将是影响竞争细菌（抗生素）和宿主生物体（影响真核细胞的分子，可能在神经学或肿瘤学中使用）的分子。我们将采取理性的，假设驱动的方法来理解和利用共生相互作用。在本提案中，我们将重点关注美国沿海沃茨中动物和细菌之间的关联。在那里，我们发现了特定的共生细菌，它们能合成各种各样的新的生物活性化合物。我们试图了解这些相互作用，同时获得新的化合物作为治疗剂的进一步发展。我们的目标是：1）了解天然产品如何塑造共生相互作用。我们将专注于不同门的海洋无脊椎动物及其相关的，可培养的细菌之间的特定相互作用。2)从培养的细菌中发现新的天然产品。我们将使用代谢组学的方法来快速磨练在以前未知的天然产物。迄今为止，这些化合物已被证明是非常活跃的，包括具有新碳骨架的新化合物。我们将专注于威斯康星州和犹他州大学的创新抗生素和神经活性测定。我们还将开发可以更广泛筛选的图书馆。3)开发天然产品用于治疗人类疾病。我们将联合收割机结合化学和生物技术方法来评估新发现药剂的前景并将其推向应用。我们将开始与一些先导化合物已经发现在我们的实验室，然后使用建立管道的其他代理人发现在这个项目中。