Genome Evolution, Innovation and Adaptation in the Apicomplexa

顶端复合体的基因组进化、创新和适应

• 批准号: 7558296
• 负责人: Jessica C Kissinger
• 金额: $ 32.31万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558296
• 关键词: Address; Affect; Algae; Amaze; Animals; Apicomplexa; Bacteria; Behavior; Bioinformatics; Biology; Child; Classification; Communities; Complex; Conflict (Psychology); Cryptosporidium; Cryptosporidium parvum; DNA; DNA Sequence Rearrangement; Data; Databases; Deposition; Disease; Distant; Drug resistance; Elements; Event; Evolution; Expressed Sequence Tags; Gene Combinations; Gene Family; Gene Proteins; Gene Transfer; General Practitioners; Genes; Genetic; Genetic Materials; Genetic Recombination; Genome; Genomics; Human; Immune; Indium; Light; Location; Malaria; Maps; Metabolic; Metabolism; Methods; Minor; Mobile Genetic Elements; Molecular; Mutation; Noise; Organelles; Organism; Orthologous Gene; Pan Genus; Parasites; Pathway interactions; Pattern; Phylogenetic Analysis; Phylogeny; Plasmodium; Plasmodium falciparum; Process; Property; Publications; Recording of previous events; Red Algae; Relative (related person); Repetitive Sequence; Reporting; Research; Research Personnel; Resources; Rest; Ribosomal RNA; Role; Signal Transduction; Source; Specificity; Symbiosis; Synteny; Taxon; Tertiary Protein Structure; Testing; Therapeutic; Toxoplasma; Toxoplasma gondii; Vertebrates; base; genome sequencing; innovation; insight; man; member; new therapeutic target; novel; novel therapeutics; paralogous gene; pathogen; programs; therapeutic target

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.

描述(申请人提供)：由单细胞寄生生物引起的疾病属于真核生物门尖端复合体，是出了名的难以治疗。这一门中最突出的生物是疟疾的病原体疟原虫，以及与艾滋病相关的病原体弓形虫和隐孢子虫。目前对这些微生物的治疗，如果它们存在，就会受到耐药性出现的威胁，或者疗效有限。其后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征：病原体中的靶分子/途径与宿主中的类似分子/途径完全不同，因此可以区分治疗化合物。Apicomplexan寄生虫和我们一样，是真核生物。因此，可供治疗师区分的新靶点较少。然而，顶端复合体寄生虫有一段多变的进化史，涉及到红藻的内生共生以及来自该藻类和其他细菌的大量基因转移。这些进化中的遥远遗传物质来源可以提供潜在的新治疗靶点。挑战在于找到他们。对顶端复合体病原体的代谢、免疫逃避和宿主适应能力进行了系统的、进化的基因组搜索。这里描述的实验计划利用了Apicomplexa复杂的进化史，以及大量寄生虫及其人类宿主基因组序列数据的增加。将调查新的寄生虫能力的起源，以及由于特定代谢或逃避能力的获得或丧失而产生的对宿主的创新和适应的类型。我们将探索顶端复合体寄生虫显著遗传可塑性的分子机制，特别是可移动和重复的DNA元件在这些过程中的可能作用。最后，这项研究将揭示这一门的新陈代谢过程存在、不存在或与其人类宿主显著不同。综上所述，这种方法应该会对Apicomplexa的基本生物学有相当大的帮助，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出版和存放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。