Oxygen Sensing by the AIDS Opportunist Pathogen, Toxoplasma gondii

艾滋病机会病原体弓形虫的氧感应

• 批准号: 8923613
• 负责人: Ira J Blader
• 金额: $ 24.43万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-04 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923613
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Address; Alleles; Amino Acids; Biochemical; Biological Assay; Brain; Brain region; Carbon Dioxide; Cell Survival; Cell physiology; Cells; Complex; Data; Dioxygenases; Disease; Distant; Drug Targeting; Environment; Enzymes; Fetus; Genes; Genetic; Genome; Goals; Growth; Homologous Gene; Hydroxylation; Immune; Immune system; In Vitro; Individual; Infection; Intestines; Knock-out; Libraries; Life Cycle Stages; Metabolism; Opportunistic Infections; Organism; Oxygen; Parasites; Patients; Peripheral; Plasmodium; Process; Procollagen-Proline Dioxygenase; Proline; Property; Publishing; Research; Retina; Series; Signal Transduction; Substrate Specificity; Succinates; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Work; alpha ketoglutarate; glycosyltransferase; homologous recombination; in vitro activity; in vivo; inhibitor/antagonist; link protein; novel; pathogen; public health relevance; research study; sensor; small molecule; ubiquitin ligase

 DESCRIPTION (provided by applicant): Toxoplasma gondii is an important opportunistic infection in AIDS patients and other immune- compromised individuals as well as fetuses. The parasite causes a broad spectrum of disorders in a variety of tissues including the brain and retina. The parasite has a complex life cycle during which it encounters diverse O2 environments. These include tissues with low O2 tensions such as the intestine, which is the first tissue that comes in contact with the parasite, and peripheral tissues such as regions of the brain that are distant from the vasculature. Adapting to changes in O2 availability is a critical cellular process for all respiring cells and organisms. How Toxoplasma senses O2 is unknown but our published and additional preliminary data indicate that this is critical for parasite growt. Cytoplasmic prolyl 4-hydroxylases (PHDs) are key cellular O2 sensors in metazoans and other protists that function by catalyzing the transfer of one atom from O2 to a protein-linked proline residue and the second one to -ketoglutarate yielding succinate, CO2 and a hydroxylated proline residue. We have identified two PHDs in Toxoplasma and our data suggests that one of these TgPhyB is an essential enzyme that can hydroxylate SKP1, which is a subunit of the E3SCF ubiquitin ligase complex. The goal of this proposal is to define the essentiality of TgPhyB, determine its substrate specificity, and identify TgPhyB inhibitors. Successful completion of these aims will unveil a novel signaling mechanism in Toxoplasma and establish how and why Toxoplasma O2 sensing is important for growth. Most importantly, this work could potentially reveal a new drug target to treat this critical opportunistic infection of AIDS patients.

 描述（由适用提供）：弓形虫Gondii是艾滋病患者和其他免疫受损的个体和胎儿的重要机会感染。寄生虫在包括大脑和视网膜在内的多种组织中引起各种各样的疾病。寄生虫具有复杂的生命周期，在此期间它遇到了潜水的O2环境。其中包括具有低O2张力的组织，例如肠道，这是与寄生虫接触的第一个组织，以及外周组织，例如远离脉管系统的大脑区域。适应O2可用性的变化是所有呼吸细胞和组织的关键细胞过程。如何弓形虫感觉O2尚不清楚，但是我们发布的和其他初步数据表明这对于寄生虫生长至关重要。细胞质脯氨酰4-羟化酶（PHD）是后生动物和其他生物中的关键细胞O2传感器，通过催化一个原子从O2转移到蛋白质连接的脯氨酸保留，第二个原子转移到第二个原子，第二个原子转移至-酮酸盐酸盐盐肥大的肥大，CO2，CO2和hydroxylated propined propine propine proline retentredention。我们已经确定了弓形虫中的两个PHD，我们的数据表明，其中一种TGPHYB是一种必不可少的酶，可以羟基化SKP1，这是E3SCF泛素连接酶复合物的亚基。该提案的目的是定义tgphyb的重要性，确定其底物特异性并确定tgphyb抑制剂。这些目标的成功完成将在弓形虫中揭示出一种新型的信号传导机制，并确定弓形虫O2敏感性如何以及为什么对生长很重要。最重要的是，这项工作可能揭示出一种新的药物靶标，以治疗艾滋病患者的这种关键机会感染。