Marine Natural Products

这是一个新的研究组成部分的竞争性更新申请，继续探索分离的天然产物抑制剂的致癌作用。在该项目中，将使用最近建立的方法从深海微生物中寻找新的抑制剂。该项目的具体目标是： - 从美国加勒比海、墨西哥湾、美国太平洋沿岸（包括阿拉斯加）、夏威夷和关岛分离新的深海沉积物衍生微生物。在适当的情况下，通过系统发育方法，使用细菌的16 S rRNA基因序列比对和真菌的18 S rRNA基因序列比对来鉴定这些微生物。 - 培养至少3，000种不同的深海微生物，用于该计划生物测定中的提取物筛选。由于每种培养物都在4种不同的条件下生长，因此在5年的资助期内将产生12，000个测试样本。 - 通过生物测定指导的分级分离，分离在环加氧酶1和2、醌还原酶、芳香酶、细胞分化、诱导凋亡和基于报告基因（ERE、NF-κ B、PPAR、ARE）的生物测定中具有显著活性的新分子。 - 通过大规模培养支持新的海洋微生物致癌抑制剂的药物开发，为临床前药理学提供高达克数量的新分子。 - 通过提供用于结构修饰或半合成的起始材料化合物参与。 - 当结构新奇和生物活性特征需要时，进行菌株改良、突变和培养物修饰实验，以产生相关代谢产物。

This is a new research component of a competitive renewal application to continue to explore the isolation of natural product inhibitors of carcinogenesis. In this project, new inhibitors will be sought from deep ocean-derived microorganisms using methods recently established. The specific goals of the project are: - To isolate new, deep ocean sediment-derived microorganisms from US locations in the Caribbean, the Gulf of Mexico, the Pacific Coast of the US (including Alaska), Hawaii and Guam. To identify these organisms, when appropriate, by phylogenetic methods using 16S rRNA gene sequence alignment for bacteria, and possibly 18S rRNA gene sequence alignments for fungi. - To cultivate at least 3,000 diverse deep sea microorganisms for extract screening in the Program bioassays. Since each culture is grown under 4 different conditions, 12,000 testing samples will be generated over the 5-year grant period. - To isolate, by bioassay-guided fractionation, new molecules with significant activity in the cyclo-oxygenase 1 and 2, quinone reductase, aromatase, cell differentiation, induction of apoptosis, and reporter gene based (ERE, NF-kB, PPAR, ARE) bioassays. - To support the pharmaceutical development of new marine microbial inhibitors of carcinogenesis by mass scale cultivation to supply up to gram quantities of new molecules for preclinical pharmacology. - To participate by supplying starting material compounds for structure modification or semisynthesis. - To undertake strain improvement, mutation and culture modification experiments to produce related metabolites when structural novelty and bioactivity profiles warrant.