Functional Characterization of the Schistosome Tegument

血吸虫体皮的功能表征

• 批准号: 7986907
• 负责人: Patrick J Skelly
• 金额: $ 41.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986907
• 关键词: Adenosine; Adopted; Alkaline Phosphatase; Applications Grants; Attenuated; Back; Biochemical; Biochemistry; Blood; Cause of Death; Cells; Cellular biology; Chronic; Cleaved cell; Complex; Country; Coupled; Data; Disease; Environment; Enzymes; Gene Expression; Genes; Gold; Grant; Hemostatic Agents; Hemostatic function; Hydrolysis; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Intervention; Knowledge; Life; Measures; Mediating; Mediator of activation protein; Membrane; Metabolic; Methods; Molecular; Monitor; Movement; Nucleotides; Nutrient; Parasite Control; Parasites; Permeability; Pharmaceutical Preparations; Phospholipids; Pichia; Platelet Activating Factor; Platyhelminths; Praziquantel; Predisposition; Property; Proteins; Purines; Pyrimidine; Pyrimidines; RNA Interference; Reaction; Recombinant Proteins; Recombinants; Relative (related person); Role; Schistosoma; Schistosome Parasite; Schistosomiasis; Signal Transduction; Signaling Molecule; Site; Sphingomyelinase; Stream; Stress; Surface; System; Techniques; Testing; Time; Vertebrates; Water; Work; analog; comparative; design; disability; ectoADPase; follow-up; functional genomics; human disease; immunoregulation; improved; in vivo; killings; novel; phosphoric diester hydrolase; public health relevance; purine; research study; response; uptake; wasting; water channel

DESCRIPTION (provided by applicant): Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting over 200 million people in over 70 countries. The parasites live for years, sometimes decades, in what should be a very hostile environment - the blood of vertebrates - yet they appear to solicit little if any protective reaction from two of the host's major defensive systems: the hemostatic system and the immune system. We hypothesize that proteins at the host-interactive surface are central to the parasites ability to dampen host immunity and hemostasis while, at the same time, permitting metabolite exchange. In this competing renewal, we propose to use new molecular methods such as RNA interference that were first developed for use with schistosomes under our previous grant, RO1 AI056273, to test several key hypotheses concerning: 1) the role of tegumental ecto-enzymes in hemostasis and immunomodulation, 2) the ability of tegumental sphingomyelinase to alter permeability properties at the parasite surface, and 3) the molecular mechanisms of trans- tegumental metabolite exchange. The functional genomics approach we adopt here coupled with independent and direct, follow-up experiments employing more traditional cell biology and biochemistry techniques are designed to provide significant new information concerning the schistosome host interactive surface. In addition the work is designed to identify tegumental proteins critical for parasite survival in the host and subsequent screens will be undertaken to discover drugs that inhibit these molecules. In this way, our planned experiments have the potential to reveal novel and valid targets, as well as new treatments, for intervention in a parasite that remains a widespread and major cause of human disease. PUBLIC HEALTH RELEVANCE: Schistosomes are parasite worms that live in the blood streams of over 200 million people in more than 70 countries. These parasites are a major cause of death and disability worldwide. The worms have remarkable properties that allow them live inside people for many years. These properties include an ability to block our immune responses from targeting them, an ability to take in nutrients from our blood and an ability to detect environmental stresses and respond appropriately. By understanding more precisely how the parasites achieve these ends, we aim to block these capabilities and kill the worms.

描述（由申请人提供）：血吸虫是一种寄生性扁形虫，可引起一种慢性、使人衰弱的疾病，困扰着70多个国家的2亿多人。这些寄生虫可以在一个非常恶劣的环境中生活数年，有时甚至数十年--脊椎动物的血液--但它们似乎对宿主的两个主要防御系统（止血系统和免疫系统）几乎没有任何保护性反应。我们推测，蛋白质在主机相互作用的表面是中央寄生虫的能力，抑制宿主免疫和止血，而在同一时间，允许代谢物交换。在这种竞争性的更新中，我们建议使用新的分子方法，如RNA干扰，这些方法最初是在我们以前的资助RO 1 AI 056273下开发的，用于检测以下几个关键假设：1）表皮胞外酶在止血和免疫调节中的作用，2）表皮鞘磷脂酶改变寄生虫表面渗透性的能力，（3）跨皮层代谢物交换的分子机制。我们在这里采用的功能基因组学方法，再加上独立和直接的，后续的实验，采用更传统的细胞生物学和生物化学技术的目的是提供重要的新信息，有关的麻烦的主机交互表面。此外，这项工作旨在确定对寄生虫在宿主中生存至关重要的被膜蛋白，随后将进行筛选以发现抑制这些分子的药物。通过这种方式，我们计划的实验有可能揭示新颖且有效的靶点以及新的治疗方法，以干预仍然是人类疾病广泛和主要原因的寄生虫。 公共卫生相关性：血吸虫是寄生蠕虫，生活在70多个国家2亿多人的血液中。这些寄生虫是全世界死亡和残疾的主要原因。这种蠕虫具有非凡的特性，使它们能够在人体内生活多年。这些特性包括阻止我们的免疫反应靶向它们的能力，从血液中吸收营养的能力以及检测环境压力并做出适当反应的能力。通过更精确地了解寄生虫如何实现这些目的，我们的目标是阻止这些能力并杀死蠕虫。