Structure and Function of Schistosome Neuropeptide F

血吸虫神经肽F的结构和功能

• 批准号: 7032341
• 负责人: Timothy A Day
• 金额: $ 28.43万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7032341
• 关键词: RNase protection assay; Schistosoma; anthelmintics; bioinformatics; biological signal transduction; cell surface receptors; confocal scanning microscopy; drug discovery /isolation; electron microscopy; high performance liquid chromatography; high throughput technology; in situ hybridization; invertebrate hormone; laboratory mouse; muscle function; neural transmission; neuromuscular system; neuropeptide Y; neuropeptides; northern blottings; polymerase chain reaction; protein purification; protein structure function; receptor expression; schistosomiasis

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形虫寄生虫，全世界至少有2亿人受到影响。由于该疾病主要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体影响。世界卫生组织的热带病研究和培训特别计划（TDR）将血吸虫病列为其五大疾病优先事项之一，并将对寄生虫的基础生物学研究确定为首要需求。吡喹酮是目前世界上大部分地区唯一可用于治疗血吸虫病的药物，但越来越多的报道表明寄生虫对这种药物的敏感性降低。因此，迫切需要鉴定新型药物的潜在靶点，以使目前患有该疾病的人受益，并控制该疾病再次出现和变得更加广泛。大多数治疗寄生蠕虫的药物都会损害它们协调肌肉活动的能力。已知的是，肌小体中的肌肉活动由肽调节，肽被称为神经肽，因为它们由其神经系统释放。这些神经肽中的一个家族，称为FMRFamide样肽或FLP，通过其直接作用于在溶酶体肌肉上发生的受体，在控制溶酶体肌肉活动中起主要作用;这些肽与溶酶体肌肉的相互作用引起快速收缩。由于这种肽家族在人类中没有很好的代表性，但在寄生虫运动中发挥着重要作用，我们建议解开FLP活性在寄生虫体内的关键方面，并在这样做的过程中，发现新的药物靶点，可以迅速导致新药的发现和随后改善这些重要寄生虫的控制。要做到这一点，我们将表征的染色体FLP和肌肉为基础的受体与它相互作用。一旦我们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蠕虫生物学中的特定作用。在此过程中，我们将准备FLP受体在高通量系统中表达，这将有助于下游药物发现工作。通过这种方式，该项目旨在产生关于染色体的基础生物学的新信息，同时，通过缩短任何潜在的化疗结果的途径，开始努力利用这些发现。