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Oxygen Sensing by the AIDS Opportunist Pathogen, Toxoplasma gondii

艾滋病机会病原体弓形虫的氧感应

基本信息

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
项目类别：
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

项目摘要

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.