Genome Evolution, Innovation and Adaptation in the Apicomplexa

描述（由申请人提供）：由属于真核生物门顶复门（Apicomplexa）的单细胞寄生生物体引起的疾病是众所周知的难以治疗的。该门中最突出的生物体是疟疾的病原体疟原虫（Plasmodium）和与艾滋病相关的病原体弓形虫（Toxoplasma）和隐孢子虫（Cryptosporidium）。目前对这些生物体的治疗方法，当它们存在时，受到耐药性出现的威胁或疗效有限。其后果是，每年有数百万人，主要是儿童死亡。需要新的治疗方法。所有良好的治疗靶标都具有一个共同的特征;病原体中的靶分子/途径与宿主中的类似分子/途径充分不同，使得可以区分治疗化合物。顶复门寄生虫，像我们一样，是真核生物。因此，可用于治疗的新靶点较少。然而，顶复门寄生虫有一个多事的进化历史，涉及内共生的一个红色的寄生虫和许多基因转移从寄生虫和其他细菌。这些遗传物质的进化遥远来源可以提供潜在的新治疗靶点。挑战是找到它们。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apicomplexan病原体提出。这里描述的实验计划利用了Apicomplexa复杂的进化历史和许多寄生虫及其人类宿主的基因组序列数据的增加。新的寄生虫能力的起源和类型的创新和适应主机创建的增益或特定的代谢或逃避能力的损失将进行调查。顶复门寄生虫的显着遗传可塑性的分子机制，特别是在这些过程中的移动的和重复的DNA元素的可能作用将被探讨。最后，这项研究将揭示代谢过程，存在，不存在，或显着不同的属这个门相对于他们的人类宿主。总的来说，这种方法应该对Apicomplexa的基础生物学有相当大的了解，揭示潜在的新治疗靶点，并测试关于真核基因组如何进化的几个重要假设。这些研究的结果将通过在社区数据库和生物信息学资源中心的出版和沉积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.