Genome Evolution, Innovation and Adaptation in the Apicomplexa

顶端复合体的基因组进化、创新和适应

基本信息

批准号：
7756591
负责人：
Jessica C Kissinger
金额：
$ 32.23万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7756591
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 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

项目摘要

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（由申请人提供）：由属于真核顶复门的单细胞寄生生物引起的疾病众所周知难以治疗。该门中最重要的生物体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。目前针对这些生物体的治疗方法，即使存在，也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（主要是儿童）死亡。需要新的疗法。所有好的治疗靶点都有一个共同点：病原体中的靶分子/途径与宿主中的相似分子/途径充分不同，使得可以区分治疗化合物。顶复门寄生虫和我们一样，都是真核生物。因此，可供治疗区分的新靶点较少。然而，顶复门寄生虫有着丰富的进化历史，涉及红藻的内共生以及来自藻类和其他细菌的大量基因转移。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。挑战是找到他们。提出了对顶端复门病原体的代谢、免疫逃避和宿主适应能力进行系统的、进化的基因组搜索。这里描述的实验计划利用了顶端复合体的复杂进化历史以及许多寄生虫及其人类宿主的基因组序列数据的可用性的增加。将研究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创新和适应宿主的类型。将探讨顶复门寄生虫显着遗传可塑性的分子机制，特别是移动和重复 DNA 元件在这些过程中的可能作用。最后，这项研究将揭示该门属相对于人类宿主存在、不存在或显着不同的代谢过程。总而言之，这种方法应该对顶端复合体的基础生物学有很大的启发，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社区数据库和生物信息学资源中心的出版和保存与更大的研究社区共享。