Structure and Function of Schistosome Neuropeptide F

血吸虫神经肽F的结构和功能

基本信息

批准号：
6922631
负责人：
Timothy A Day
金额：
$ 30.57万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2010-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by the applicant): Schistosomes are flatworm parasites that cause schistosomiasis, which afflicts at least 200 million people worldwide. Since the disease is focused among underprivileged children in developing countries, it is very difficult to assess the total impact of the disease. The World Health Organization's Special Program for Research and Training in Tropical Diseases (TDR) considers schistosomiasis among its top five disease priorities, and identifies research into the basic biology of schistosome parasites as a primary need. Praziquantel is presently the only drug available for the treatment of schistosomiasis in most parts of the world, but there are growing reports of decreased sensitivity of parasites to this drug. Thus, there is an urgent need to identify potential targets for novel drugs, both for the benefit of those presently suffering from the disease, and to control the disease from re-emerging and becoming more widespread. Most of the available drugs that treat parasitic worms compromise their ability to coordinate muscle activity. It is known that muscle activity in schistosomes is modulated by peptides, designated neuropeptides because they are released by its nervous system. One family of these neuropeptides, designated the FMRFamide-like peptides or FLPs, plays a major role in the control of schistosome muscle activity through its direct actions on a receptor that occurs on schistosome muscle; the interaction of these peptides with schistosome muscle causes a rapid contraction. Since this peptide family is not well represented in humans and yet plays a fundamental role in parasite movement, we propose to unravel key facets of FLP activity in schistosomes and, in so doing, uncover new drug targets that could rapidly lead to novel drug discovery and subsequent improved control of these important parasites. To do this, we will characterize the schistosome FLP and the muscle-based receptor with which it interacts. Once we have identified these key molecules, we will proceed to investigate their distribution within the worm, the mechanisms they use to cause muscle contraction and their specific role within schistosome biology. During this process, we will prepare the FLP receptor for expression in a high throughput system that will facilitate downstream drug discovery efforts. In this way, this project intends to generate novel information on the basic biology of schistosomes and, at the same time, initiate efforts to exploit these discoveries by shortening the route to any potential chemotherapeutic outcomes.

描述（由申请人提供）：血吸虫是引起血吸虫病的扁虫寄生虫，在全球至少遭受了至少2亿人。由于该疾病集中在发展中国家的贫困儿童中，因此很难评估该疾病的总影响。世界卫生组织的热带疾病研究和培训特别计划（TDR）认为血吸虫病是其前五名的重点，并确定对Schistosos寄生虫的基本生物学的研究是主要需求。 Praziquantel目前是世界上大部分地区可用于治疗血吸虫病的唯一药物，但越来越多的报道称寄生虫对这种药物的敏感性降低。因此，迫切需要确定新型药物的潜在靶标，既是为了使患有该疾病的人的受益，又要控制疾病重新出现并变得更加广泛。处理寄生虫蠕虫的大多数可用药物都会损害其协调肌肉活动的能力。众所周知，血吸虫中的肌肉活性是由指定神经肽的肽调节的，因为它们是由其神经系统释放的。这些神经肽的一个家族称为FMRFAMIDE样肽或FLP，通过其直接作用在螺杆菌肌肉上发生的受体来控制棘小肌肉活性，在控制螺杆菌肌肉活动中起着重要作用。这些肽与黑素肌肉的相互作用会引起快速收缩。由于该肽家族在人类中没有很好地代表，但在寄生虫运动中起着基本作用，因此我们建议揭开血块中FLP活性的关键方面，并且在这样做的过程中，揭示了可以快速导致新型药物发现的新药物靶标，并随后对这些重要寄生虫的改善控制。为此，我们将表征Schistosoms FLP及其相互作用的基于肌肉的受体。一旦确定了这些关键分子，我们将继续研究它们在蠕虫中的分布，它们用于引起肌肉收缩的机制以及它们在Schistosom生物学中的特定作用。在此过程中，我们将准备FLP受体在高吞吐量系统中表达，这将有助于下游药物发现工作。通过这种方式，该项目旨在生成有关血吸虫基本生物学的新颖信息，同时，通过将途径缩短到任何潜在的化学治疗结果，从而启动了利用这些发现的努力。