Ecdysteroid Signaling in Filarial Parasites

丝虫寄生虫中的蜕皮类固醇信号传导

• 批准号: 8581279
• 负责人: THOMAS R UNNASCH
• 金额: $ 21.76万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581279
• 关键词: Adult; Adverse effects; Affect; Agonist; Agriculture; Area; Attention; Biological Assay; Biological Factors; Child; Clinical; Communities; Data; Development; Developmental Process; Disease; Drug Design; Drug Targeting; Ecdysone; Ecdysteroids; Embryonic Development; Failure; Family; Female; Foundations; Goals; Health; Homologous Gene; Human; Industry; Infection; Infection Control; Insecta; Insecticides; International; Laboratories; Lead; Libraries; Life; Malaria; Mediating; Microfilaria; Molting; NIH 3T3 Cells; Organism; Parasites; Pathway interactions; Personal Satisfaction; Pharmaceutical Preparations; Play; Public Health; Reproduction; Reproductive Process; Resistance development; Role; Series; Signal Transduction; Staging; Sterilization; System; Tetracyclines; Transfection; Treatment Protocols; Tropical Disease; Vertebrates; Woman; analog; chemotherapeutic agent; disability-adjusted life years; ecdysone receptor; economic impact; filaria; global health; high throughput screening; member; novel; pregnant; programs; public health relevance; response; screening; socioeconomics; success; transmission process

DESCRIPTION (provided by applicant): Diseases caused by the human filarial parasites are a serious global health problem. The large socio- economic impact of these diseases has attracted the attention of the international community, which has supported several programs to control these infections. These programs rely upon mass distribution of a very limited number of drugs, all of which must be given repeatedly over a period of years to control transmission, as they primarily affect the larval stage of the parasite (the microfilariae). The need for prolonged repeated treatment is logistically difficult and leaves the programs vulnerable to failure if resistance develops. Thus, there is a clear need for new drugs to supplement the microfilaricides currently available. Experimental and clinical evidence suggest that drugs that target the adult female's reproductive processes, resulting in sterilization, would be particularly desirable. Filaria are classified as ecdysozoans, organisms whose development is characterized by a series of molts from one stage to another. Most studies of ecdysozoan development have concentrated on insects. A central developmental regulator in insects is the ecdysone receptor (EcR), which plays a role in embryogenesis and other developmental processes, in addition to controlling molting. The EcR has been exploited as a target by the agricultural industry, which has developed insecticidal ecdysone analogs that are very toxic to their target insects but non-toxic to vertebrates. We have recently collaborated on the identification of a homolog of the EcR from the human filarial parasite B. malayi. This represents the first defined regulator involved in filarial development. The success in developing highly effective EcR analog insecticides which are non-toxic to off-target organisms underscores the potential of the EcR as a chemotherapeutic target for human filarial infections. Furthermore, the indirect evidence suggesting that ecdysteroids may be important in filarial embryogenesis suggests that compounds targeting the EcR may disrupt parasite reproduction. The overall goal of this project will be to investigate the potential of the filarial EcR as a chemotherapeutic target. To accomplish this goal, we propose the following specific aims: 1. To adapt our existing assay to a high throughput screening format for identification of agonists and antagonists of the B. malayi ecdysone receptor (BmEcR). 2. To screen a natural products library and two ecdysteroid analog libraries for BmEcR agonists and antagonists. 3. To evaluate the effect of the lead BmEcR agonists and antagonists on B. malayi parasites in culture.

描述（由申请人提供）：由人类肺寄生虫引起的疾病是一个严重的全球健康问题。这些疾病的巨大社会经济影响吸引了国际社会的关注，国际社会支持了几种控制这些感染的计划。这些程序依赖于数量非常有限的药物的质量分布，所有这些药物都必须在多年的时间内反复给予，以控制传播，因为它们主要影响寄生虫的幼体阶段（微丝菌）。长时间重复治疗的需求在逻辑上很困难，并且如果阻力发展，这些程序很容易受到失败的影响。因此，很明显需要新药补充当前可用的微椰胶苷剂。实验和临床证据表明，针对成年女性生殖过程的药物尤其是灭菌的药物 理想。 Filaria被归类为Ecdysozoans，其发育的特征是从一个阶段到另一个阶段的一系列蜕皮。大多数关于Ecdysozoan发育的研究都集中在昆虫上。昆虫中的中央发育调节剂是ecdysone受体（ECR），它在胚胎发生和其他发育过程中发挥作用，此外还控制了摩擦。 ECR已被农业产业利用为目标，农业产生了杀虫性的ecdysone类似物，这些类似物对其靶昆虫非常有毒，但对脊椎动物无毒。最近，我们合作鉴定了人类丝状寄生虫B. Malayi的ECR同源物。这代表了涉及的第一个定义的调节器 丝状发育。开发高效的ECR类似杀虫剂的成功，这些杀虫剂对靶向生物无毒，这突显了ECR作为人丝状感染的化学治疗靶标的潜力。此外，间接证据表明，在丝状胚胎发生中可能很重要，这表明靶向ECR的化合物可能会破坏寄生虫的繁殖。该项目的总体目标是研究丝状ECR作为化学治疗靶标的潜力。为了实现这一目标，我们提出了以下特定目的：1。将现有的测定法调整到高吞吐量筛选格式中，以鉴定马来芽孢杆菌Ecdysone受体（BMECR）的激动剂和拮抗剂。 2。筛选天然产品库和两个用于BMECR激动剂和拮抗剂的ecdysteroid模拟库。 3。评估铅Bmecr激动剂和拮抗剂对培养物中马来语寄生虫的影响。