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

基本信息

批准号：
8562698
负责人：
Eric W Schmidt
金额：
$ 30.46万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-02 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8562698
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

项目摘要

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会与细菌相互作用。在许多情况下，在古老的共生过程中，细菌进化出了特定的小分子天然产物，以与其宿主生物体和其他竞争微生物相互作用。这些化合物具有极高的生物活性，有些甚至是 FDA 批准的用于治疗癌症等疾病的药物。这些分子可能与许多不同动物体内的分子靶标共同进化，这意味着它们是通过进化而选择的，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人们所理解，并且代表着一个实际上尚未开发的储库，可以用于发现具有治疗人类疾病潜力的药物。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（影响真核细胞并可能在神经病学或肿瘤学中使用的分子）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。在这项提案中，我们将重点关注美国沿海水域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，它们可以合成意想不到的多种新的生物活性化合物。我们寻求了解这些相互作用，同时获得新的化合物以进一步开发为治疗剂。我们的目标是：1）了解天然产品如何塑造共生相互作用。我们将重点关注海洋无脊椎动物不同门及其相关的可培养细菌之间的特定相互作用。 2) 从培养细菌中发现新的天然产物。我们将使用代谢组学方法快速研究以前未知的天然产物。迄今为止，这些化合物已被证明具有极高的活性，并且包括具有新碳骨架的新化合物。我们将重点关注威斯康星大学和犹他大学提供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库。 3）开发用于治疗人类疾病的天然产物。我们将结合化学和生物技术方法来评估新发现的药物的前景并将其推向应用。我们将从我们实验室中已经发现的一些先导化合物开始，然后使用已建立的管道来研究该项目中发现的其他药物。