Comparative and functional genomics of Toxoplasma and Hammondia hammondi

弓形虫和 Hammondia hammondi 的比较和功能基因组学

基本信息

批准号：
10669739
负责人：
JON P BOYLE
金额：
$ 38.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669739
关键词：
Acute Adopted Adult Animal Model Animals Antiparasitic Agents Automobile Driving Biology Candidate Disease Gene Cell Aging Cell Cycle Cells Child Complement Cyst DNA Damage Data Development Developmental Gene Disease Fetal Development Foundations Funding Gene Expression Regulation Genes Genetic Goals Growth Growth and Development function HIV/AIDS Host Defense Immune response Immunosuppression Infection Inflammatory Inflammatory Response Innate Immune Response Life Cycle Stages Link Masks Modeling Molecular Organism Outcome Parasites Pathogenesis Pathway interactions Patients Persons Phenotype Placenta Predisposition Refractory Regulation Regulatory Pathway Signal Pathway Sporozoites Stress Synteny System Testing Therapeutic Intervention Toxoplasma Toxoplasma gondii Toxoplasmosis Transgenic Organisms Virulence Virulence Factors Work comparative comparative genomics epigenomics experience experimental study follow-up functional genomics genetic approach human disease human pathogen in vitro Assay innovation knockout gene new therapeutic target novel novel therapeutic intervention nucleic acid binding protein obligate intracellular parasite opportunistic pathogen prevent response success trait transcriptome sequencing transcriptomics virulence gene

项目摘要

PROJECT SUMMARY/ABSTRACT: Toxoplasma gondii is an important opportunistic pathogen of humans where it can cause severe disease in the developing fetus and those with HIV/AIDS. Parasite development is critical for its ability to cause severe disease, yet the precise mechanisms for how it does this are poorly understood. T. gondii is also modulates the cell that in infects via secretion of a multitude of effectors. Much of the work aimed at understanding how T. gondii is able to cause disease has focused exclusively on T. gondii itself. An innovative alternative to this approach is to perform functional and genetic comparisons between T. gondii and its near relatives to reveal previously unknown mechanisms of parasite virulence and developmental regulation. The parasite Hammondia hammondi is one such relative, and our work in the prior funding period has developed this organism into a powerful comparative model for probing T. gondii biology from an evolutionary context. In this renewal we follow up on two observations from the prior funding period: 1) that T. gondii is unique in its ability to facultatively regulate its conversion to the quiescent cyst stage and 2) that T. gondii is unique in its ability to alter the host cell cycle and that this may be linked to suppression of host anti-parasitic responses. In Aim 1 we use a focused RNAseq screen to identify new regulators of T. gondii development, using H. hammondi as a natural filter to focus on relevant candidate genes. Success of this Aim is facilitated by the use of new transgenic approaches for H. hammondi and preliminary data supporting the premise of our candidate based approach. In Aim 2 we determine how T. gondii and H. hammondi differentially regulate changes in the infected host cell, with a focus on underappreciated host pathways including DNA damage responses and cellular senescence. Success of this aim is facilitated by our extensive experience with T. gondii and H. hammondi sporozoites and in vitro assays, as well as transgenic approaches in H. hammondi that will permit us to perform the first ever cross-species complementation experiments in this organism. Overall these studies build on work during the prior funding period aimed at identifying important phenotypic differences between these closely related parasite species and then determining their molecular mechanisms. We expect these studies to result in new discoveries of how T. gondii regulates in growth and development and how it is able to suppress a wide variety of host defenses. Both of these lines of inquiry will identify new avenues for therapeutic intervention, whether they target the parasite itself or host responses found to be critical for its survival.

项目摘要/摘要：弓形虫弓形虫是人类的重要机会性病原体，在该病原体中，它会在发展胎儿和患有艾滋病毒/艾滋病的胎儿。寄生虫的发展对于造成严重的能力至关重要疾病，但是对它如何做到的确切机制知之甚少。 T. gondii也是调制的通过分泌多种效应子在感染中的细胞。许多工作旨在了解T. Gondii能够引起疾病，仅专注于弓形虫本身。一种创新的替代方案方法是在T. gondii及其近乎亲戚之间进行功能和遗传比较以揭示以前未知的寄生虫毒力和发育调节机制。寄生虫哈蒙迪亚 Hammondi就是这样的亲戚，我们在以前的资金期间的工作已将这种生物发展成一个从进化环境中探测巨霉菌生物学的强大比较模型。在这个续约中我们跟进以前的资金期间的两个观察结果：1）T。Gondii在其能力上是独一无二的教师调节其转换为静态囊肿阶段，2）T. gondii在其能力上是独一无二的改变宿主细胞周期，这可能与抑制宿主抗寄生虫反应有关。在目标1中我们使用专注的RNASEQ屏幕以使用H. hammondi作为一个自然过滤器专注于相关候选基因。使用新目标的成功可以促进 H. Hammondi和初步数据的转基因方法支持我们基于候选人的前提方法。在AIM 2中，我们确定了T. gondii和H. Hammondi如何差异调节受感染的宿主细胞，重点是未被宿主的途径，包括DNA损伤反应和细胞衰老。我们在T. Gondii和H.的丰富经验中促进了这一目标的成功。 Hammondi Sporozoites和体外测定，以及H. Hammondi的转基因方法我们要在该生物体中进行有史以来的第一个跨物种互补实验。总体而言，这些研究在以前的资金期间建立工作，旨在确定重要的表型差异这些密切相关的寄生虫物种，然后确定它们的分子机制。我们期望这些研究导致新发现如何调节生长和发展以及如何调节其能力抑制各种各样的宿主防御。这两种询问都将确定治疗干预，无论是针对寄生虫本身还是宿主的反应，生存。