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Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi

从五大湖真菌中采购生物活性次生代谢物

基本信息

批准号：
9296148
负责人：
Robert Henry Cichewicz
金额：
$ 55.6万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296148
关键词：
Address Adult Affinity Antineoplastic Agents Back Biodiversity Biological Biological Assay Cancer cell line Cells Chemical Warfare Chemicals Chemistry Collaborations Communities Cyclosporins Cytotoxin Data Development Disease Ecology Emotional Environment Exhibits Family Fresh Water Gene Cluster Goals Growth Habitats Hybrids Knowledge Laboratories Lead Libraries Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Medical Methods Michigan Microbiology Mission Molecular Target Natural Products Natural Products Chemistry Nature Pathway interactions Pediatric Oncology Penicillins Pharmaceutical Preparations Pharmacology Preparation Process Production Reporting Research Research Personnel Resources Sampling Solid Source Specificity Talents Taxonomy Techniques Testing The science of Mycology Therapeutic Translating United States National Institutes of Health Water Water Supply Xenograft procedure base benthos bioactive natural products burden of illness design drug discovery fungus improved in vivo inhibitor/antagonist innovation innovative technologies mortality mouse model novel novel therapeutics outcome forecast product development public health relevance scale up screening success tool virtual

项目摘要

DESCRIPTION (provided by applicant): Today, many solid pediatric cancers have a poor prognosis, contributing to an immense amount of physical and emotional suffering on the parts of the victims and their families. A key development on the pathway to addressing this unmet medical need has been growing recognition that the cellular bases of most pediatric cancers are different from those regulating their adult counterparts. Therefore, drug discovery efforts focused on the identification of new therapeutic leads that target the mechanisms underpinning pediatric cancers are needed. Fundamental to the success of any effort for improving chemotherapeutic options against pediatric cancers is an approach that matches the discovery possibilities embodied in a chemically diverse library of drug-like molecules with assays probing the selectivity/specificity of disease-relevant targets. Natural products fulfill this key criterio offering a rich assortment of novel structural features that nature has evolved into bioactive compounds. Our preliminary studies demonstrate that new fungal taxa derived from Great Lakes sediments generate compounds with these types of attractive biological profiles as exemplified in preliminary studies demonstrating selective activity against pediatric cancer cell lines. Based on these data, we hypothesize that the Great Lakes contain a unique and diverse assemblage of fungi that is virtually untapped for the production of bioactive natural products with potential against childhood cancers. To achieve the goal of transforming this fungal source of biological and chemical diversity into therapeutically-promising molecules, we have assembled a collaborative network of researchers with expertise in natural products chemistry, cancer drug discovery/pharmacology, Great Lakes ecology, and mycology. We will test the central hypothesis and fulfill the objectives of this proposal through six specific aims: 1) procuring sediment samples from diverse Great Lakes environments, 2) isolating fungi from sediment samples and preparing an extract library for screening, 3) testing extracts for activities in a suite of new and disease-relevant-assays pertaining to rare yet fatal pediatric cancers, 4) prioritizing bioactive samples for scale-up studies using bioassay data, taxonomic affinity, and chemical markers, 5) purifying bioactive compounds, and 6) verifying the in vivo activities of purified compounds in xenograft mouse models. Several innovative features have been built into our approach that pertain to both the biological assays (focus on selective inhibition of enzymatic and cell targets exhibited by pediatric cancers) and natural products chemistry approaches (new methods for the semi-automated isolation of fungi, expedited extract preparation, and advanced dereplication tools). These new techniques are expected to enhance our approach to identifying new bioactive compounds. Our research is significant because many pediatric cancers remain untreatable and vigorous efforts are needed to identifying compounds with promising therapeutic profiles that address this unmet medical need. We expect that that our studies will provide several new options for further development as therapies for childhood cancers.

描述（由申请人提供）：今天，许多实体儿科癌症的预后很差，导致受害者及其家人遭受巨大的身体和情感痛苦。在解决这一未满足的医疗需求的途径上，一个关键的发展是越来越多的人认识到，大多数儿童癌症的细胞基础与调节成人癌症的细胞基础不同。因此，药物发现工作的重点是确定新的治疗线索，目标是儿童癌症的基础机制是必要的。改善儿科癌症化疗选择的任何努力取得成功的基础是一种方法，该方法将化学多样性药物样分子库中体现的发现可能性与探测疾病相关靶标的选择性/特异性的测定相匹配。天然产物满足这一关键标准，提供了丰富的新结构特征，自然界已经演变成生物活性化合物。我们的初步研究表明，新的真菌类群来自五大湖沉积物产生的化合物与这些类型的有吸引力的生物配置文件，在初步研究证明对儿科癌细胞系的选择性活性的例证。基于这些数据，我们假设五大湖含有独特而多样的真菌组合，这些真菌几乎未被开发用于生产具有抗儿童癌症潜力的生物活性天然产物。为了实现将这种生物和化学多样性的真菌来源转化为具有治疗前景的分子的目标，我们已经组建了一个具有天然产物化学，癌症药物发现/药理学，五大湖生态学和真菌学专业知识的研究人员合作网络。我们将通过六个具体目标来检验中心假设并实现本提案的目标：1）从不同的五大湖环境中获取沉积物样品，2）从沉积物样品中分离真菌并制备用于筛选的提取物库，3）测试提取物的活性在一套关于罕见但致命的儿科癌症的新的和疾病相关的测定中，4）使用生物测定数据、分类亲和性和化学标记物优先选择用于放大研究的生物活性样品，5）纯化生物活性化合物，和6）在异种移植小鼠模型中验证纯化的化合物的体内活性。我们的方法中包含了几个创新功能，涉及生物测定（专注于儿科癌症所表现出的酶和细胞靶点的选择性抑制）和天然产物化学方法（用于真菌半自动分离的新方法，加速提取物制备和先进的去复制工具）。这些新技术预计将增强我们识别新生物活性化合物的方法。我们的研究意义重大，因为许多儿科癌症仍然无法治疗，需要大力努力确定具有有希望的治疗特征的化合物，以解决这种未满足的医疗需求。我们希望我们的研究将为进一步开发儿童癌症的治疗方法提供几种新的选择。