Biology of the apicomplexan plastid

描述(由申请人提供)：复合体顶体对许多重要的人类疾病负责，包括疟疾、弓形虫病、隐孢子虫病和环孢子虫病。这些疾病的管理在很大程度上依赖于化疗，但抗寄生虫药物治疗面临多重挑战。这些问题包括总体效力差、对某些生命周期阶段的限制、不想要的副作用以及迅速出现的多重耐药。需要源源不断的新药和潜在的药物靶点，以跟上这些病原体构成的威胁。这种寄生虫特异性靶标最有希望的来源之一是顶端复合体或质外体。顶生质体是寄生虫所特有的，其功能对寄生虫的生存至关重要。这个细胞器是自由生活的光合作用历史的遗留物。顶体的结构和生物学非常复杂，因为它来自两种真核生物的内生共生结合：一种红藻和一种营养缺陷型原生生物。这项应用的目标是从机械细节上解开这一生物学的复杂性，并确定未来的干预目标。以弓形虫为模型生物，我们将通过遗传学、细胞生物学和生物化学的方法来表征在细胞器外部隔间展开的两种途径的功能，我们假设这两种途径对细胞器和寄生虫是必不可少的。我们将以更广泛的努力来补充这种有重点的方法，以定义一组全面的叶绿体蛋白质，以继续为假设驱动的机械实验管道提供强大的候选基因。

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.