Genome Evolution, Innovation and Adaptation in the Apicomplexa

描述（由申请人提供）：由真核生物顶复虫门的单细胞寄生生物引起的疾病是众所周知的难以治疗。该门中最突出的生物是疟原虫，疟疾的病原体，以及与艾滋病相关的病原体，弓形虫和隐孢子虫。当这些生物体存在时，目前对它们的治疗受到耐药性出现的威胁，或者疗效有限。其结果是每年有数百万人死亡，主要是儿童。需要新的治疗方法。所有好的治疗靶点都有一个共同的特点；病原体中的靶分子/途径与宿主中的类似分子/途径有足够的区别，从而可以区分治疗化合物。顶复合体寄生虫，像我们一样，是真核生物。因此，可供治疗区分的新靶点较少。然而，顶复合体寄生物的进化史非常丰富，包括与红藻的内共生以及从红藻和其他细菌中转移的大量基因。这些遗传物质的进化远源可以提供潜在的新治疗靶点。挑战在于找到它们。提出了一个系统的，进化的基因组搜索的代谢，免疫逃避和宿主适应能力的顶复合体病原体。本文描述的实验计划利用了顶复合体的复杂进化史，以及许多寄生虫及其人类宿主的基因组序列数据的增加。将研究寄生虫新能力的起源以及由于获得或失去特定代谢或逃避能力而产生的创新和适应宿主的类型。本研究将探讨顶复合体寄生物显著遗传可塑性的分子机制，特别是可移动和重复DNA元素在这些过程中可能发挥的作用。最后，这项研究将揭示代谢过程是存在的，不存在的，或者在这个门的属相对于他们的人类宿主显著不同。综上所述，这种方法应该对顶复合体的基本生物学有相当大的启示，揭示潜在的新治疗靶点，并测试真核生物基因组如何进化的几个重要假设。这些研究的结果将通过发表和储存在社区数据库和生物信息学资源中心与更大的研究社区共享。

DESCRIPTION (provided by applicant): Diseases caused by unicellular parasitic organisms belonging to the eukaryotic phylum Apicomplexa are notoriously difficult to treat. The most prominent organisms in this phylum are Plasmodium, the causative agent of malaria, and the AIDS-related pathogens, Toxoplasma and Cryptosporidium. Current treatments for these organisms, when they exist, are threatened by the emergence of drug resistance or are of limited efficacy. The consequence is that millions of people, primarily children, die annually. New therapeutics is needed. All good therapeutic targets have one feature in common; the target molecule/pathway in the pathogen is sufficiently distinct from similar molecules/pathways in the host such that therapeutic compounds can be discriminated between. Apicomplexan parasites, like us, are eukaryotic organisms. Thus, there are fewer novel targets available for therapeutics to discriminate between. However, apicomplexan parasites have had an eventful evolutionary history involving endo-symbiosis of a red alga and numerous gene transfers from the alga and other bacteria. These evolutionary distant sources of genetic material can provide potential new therapeutic targets. The challenge is to find them. A systematic, evolutionary genomic search of the metabolic, immune evasive and host adaptive capabilities of apicomplexan pathogens is proposed. The experimental plan described here exploits the complex evolutionary history of the Apicomplexa and the increased availability of genome sequence data for numerous parasites and their human host. The origins of novel parasite capabilities and the types of innovation and adaptation to host created by the gain or loss of particular metabolic or evasive capabilities will be investigated. The molecular mechanisms underlying the remarkable genetic plasticity of apicomplexan parasites, in particular the possible role of mobile and repetitive DNA elements in these processes will be explored. Finally, this study will reveal metabolic processes that are present, absent, or strikingly different in genera of this phylum relative to their human host. Taken together, this approach should shed considerable light on the basic biology of the Apicomplexa, reveal potential new therapeutic targets and test several important assumptions about how eukaryotic genomes evolve. The results of these studies will be shared with the larger research community via publication and deposition in community databases and Bioinformatics Resource Centers.