Biology of the apicomplexan plastid

描述（由申请人提供）：顶孢复合体负责许多重要的人类疾病，包括疟疾，弓形虫病，隐孢子虫病和环孢子虫病。这些疾病的治疗主要依赖于化疗，但抗寄生虫药物治疗面临多重挑战。这些问题包括整体效力差、局限于某些生命周期阶段、不良副作用以及迅速出现的多重耐药性。需要不断有新的药物和潜在的药物靶点来跟上这些病原体构成的威胁。这些寄生虫特异性靶点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，它的功能对寄生虫的生存至关重要。这个细胞器是过去自由生活的光合作用遗留下来的。顶质体的结构和生物学是非常复杂的，因为它来源于两个真核生物的内共生结合：一个红藻和一个营养不良的原生生物。该应用程序的目标是在机械细节上揭示这种生物学的复杂性，并确定未来的干预目标。将弓形虫作为一种模式生物，我们将运用遗传学、细胞生物学和生物化学的方法来描述在细胞器外室展开的两条途径的功能，我们假设这两条途径对细胞器和寄生虫至关重要。我们将通过更广泛的努力来补充这种专注的方法，以定义一套全面的质体蛋白，继续为具有强候选基因的假设驱动的机制实验提供管道。

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.