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（由申请人提供）：弓形虫是艾滋病患者和其他免疫受损个体以及胎儿的重要机会性感染。这种寄生虫会在包括大脑和视网膜在内的多种组织中引起广泛的疾病。该寄生虫具有复杂的生命周期，在此期间它会遇到不同的氧气环境。这些组织包括氧气张力较低的组织，例如肠道，它是第一个与寄生虫接触的组织，以及周围组织，例如远离脉管系统的大脑区域。对于所有呼吸细胞和生物体来说，适应氧气供应的变化是一个关键的细胞过程。弓形虫如何感知氧气尚不清楚，但我们发表的和额外的初步数据表明，这对于寄生虫的生长至关重要。细胞质脯氨酰 4-羟化酶 (PHD) 是后生动物和其他原生生物中关键的细胞 O2 传感器，其功能是催化一个原子从 O2 转移到蛋白质连接的脯氨酸残基，然后将第二个原子转移到 α-酮戊二酸，产生琥珀酸、CO2 和羟基化脯氨酸残基。我们在弓形虫中鉴定出两个 PHD，我们的数据表明其中一个 TgPhyB 是一种可以羟基化 SKP1 的必需酶，而 SKP1 是 E3SCF 泛素连接酶复合物的一个亚基。该提案的目标是定义 TgPhyB 的必要性、确定其底物特异性并鉴定 TgPhyB 抑制剂。这些目标的成功完成将揭示弓形虫中的一种新的信号传导机制，并确定弓形虫 O2 传感对生长的重要性及其原因。最重要的是，这项工作可能会揭示治疗艾滋病患者这种严重机会性感染的新药物靶点。