Ecdysteroid Signaling in Filarial Parasites

描述（由申请人提供）：由人类丝虫寄生虫引起的疾病是一个严重的全球性健康问题。这些疾病的巨大社会经济影响引起了国际社会的关注，国际社会支持了控制这些感染的几个方案。这些方案依赖于大量分发数量非常有限的药物，所有这些药物都必须在数年内反复使用以控制传播，因为它们主要影响寄生虫（微丝蚴）的幼虫阶段。长期重复治疗的需要在后勤上是困难的，如果出现耐药性，这些方案很容易失败。因此，显然需要新的药物来补充目前可用的杀微丝蚴剂。实验和临床证据表明，针对成年女性生殖过程的药物，导致绝育， 令人向往丝虫被归类为蜕皮动物，其发育的特征是从一个阶段到另一个阶段的一系列蜕皮。大多数关于蜕皮动物发育的研究都集中在昆虫身上。蜕皮激素受体（EcR）是昆虫的一种重要的发育调节因子，除了控制蜕皮外，它还在胚胎发生和其他发育过程中发挥作用。EcR已被农业工业开发为靶标，农业工业已经开发出对它们的靶标昆虫非常有毒但对脊椎动物无毒的杀虫蜕皮激素类似物。我们最近合作鉴定了人类丝虫寄生虫B的EcR同源物。马来语。这是第一个定义的监管机构， 丝虫的发展在开发对脱靶生物无毒的高效EcR类似物杀虫剂方面的成功强调了EcR作为人类丝虫感染的化疗靶点的潜力。此外，间接证据表明，蜕皮类固醇可能是重要的丝虫胚胎发育表明，化合物靶向EcR可能会破坏寄生虫繁殖。本项目的总体目标是研究丝虫EcR作为化疗靶点的潜力。为实现这一目标，我们提出以下具体目标：1.使我们现有的测定适应于高通量筛选形式，用于鉴定B的激动剂和拮抗剂。马来蜕皮激素受体（BmEcR）。2.筛选BmEcR激动剂和拮抗剂的天然产物库和蜕皮甾体类似物库。3.评价主要BmEcR激动剂和拮抗剂对B的影响。马来寄生虫的文化。

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.