Biology of the apicomplexan plastid

描述（由申请人提供）：顶复门是许多重要人类疾病的原因，包括疟疾、弓形虫病、隐孢子虫病和环孢子虫病。这些疾病的管理主要依赖于化疗，但抗寄生虫药物治疗面临着多重挑战。这些包括整体效力差，限制某些生命周期阶段，不必要的副作用和迅速出现的多重耐药性。为了跟上这些病原体构成的威胁，需要不断推出新的药物和潜在的药物靶标。这种寄生虫特异性靶标的最有希望的来源之一是顶复体质体或顶质体。顶质体是寄生虫所特有的，其功能对寄生虫的生存至关重要。这种细胞器是过去自由生活的光合作用的遗留物。顶质体的结构和生物学是非常复杂的，因为它来自两种真核生物的内共生婚姻：一种红球藻和一种营养缺陷型原生生物。该应用程序的目标是在机械细节中解开这种生物学的复杂性，并确定未来的干预目标。使用弓形虫作为模式生物，我们将进行遗传，细胞生物学和生物化学的方法来表征两个途径的功能，展开在细胞器的外室，我们假设是必不可少的细胞器和寄生虫。我们将通过更广泛的努力来补充这种集中的方法，以定义一套全面的质体蛋白质，以继续为假设驱动的机制实验提供强有力的候选基因。 公共卫生相关性：弓形虫是一种重要的人类病原体，可导致未出生的胎儿、幼儿和免疫系统减弱的患者患病。我们正在研究一种与植物叶绿体有关的寄生虫的独特细胞结构。对这种结构的生物学的详细了解将引导我们找到新的寄生虫特异性干预措施来治疗和预防疾病。

DESCRIPTION (provided by applicant): Apicomplexa are responsible for a number of important human diseases including malaria, toxoplasmosis, cryptosporidiosis and cyclosporidiosis. Management of these diseases rests heavily on chemotherapy but anti-parasitic drug treatment faces multiple challenges. These include poor overall potency, restriction to certain life-cycle stages, unwanted side effects, and rapidly emerging multiple drug resistance. A constant stream of new drugs and potential drug targets is required to stay abreast of the threat posed by these pathogens. One of the most promising sources of such parasite specific targets is the apicomplexan plastid or apicoplast. The apicoplast is unique to the parasite and its function is essential to parasite survival. This organelle is a holdover from a free-living photosynthetic past. The structure and biology of the apicoplast is remarkably complex as it is derived from the endosymbiotic marriage of two eukaryotes: a red alga and an auxotrophic protist. The goal of this application is to unravel the complexity of this biology in mechanistic detail and to identify future targets for intervention. Using Toxoplasma as a model organism we will conduct genetic, cell biological and biochemical approaches to characterize the function of two pathways that unfold in the outer compartments of the organelle and that we hypothesize are essential to the organelle and the parasites. We will complement this focused approach with a broader effort to define a comprehensive set of plastid proteins to continue to feed a pipeline of hypothesis-driven mechanistic experiments with strong candidate genes. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii is an important human pathogen that causes disease in the unborn fetus, young children and patients with a weakened immune system. We are a studying a unique cellular structure of the parasite that is related to the chloroplast of plants. A detailed understanding of the biology of this structure will lead us to new parasite specific interventions to treat and prevent disease.