ER-shaping proteins of Plasmodium

疟原虫的内质网塑造蛋白

基本信息

批准号：
10240941
负责人：
Purnima Bhanot
金额：
$ 66.84万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10240941
关键词：
Affect Anabolism Antimalarials Architecture Attenuated Biological Cell membrane Cells Collection Cytoplasm Data Defect Development Dissection Drug resistance Endoplasmic Reticulum Environment Equilibrium Erythrocytes Eukaryota Eukaryotic Cell Family Future Genes Goals Growth Guanosine Triphosphate Phosphohydrolases Hemoglobin Hepatic Hepatocyte Homologous Gene Immunity In Vitro Individual Infection Knowledge Length Life Style Link Liver Malaria Mammalian Cell Mass Spectrum Analysis Membrane Microscopy Molecular Morphogenesis Morphology Mus Mutation Nutrient Organelles Outcome Parasites Pathogenicity Pattern Peptides Physiology Plant Proteins Plasmodium Plasmodium berghei Play Process Protein Export Pathway Protein Secretion Proteins Proteome Protozoa RTN1 gene Resistance Resolution Role Shapes Specific qualifier value Structure Structure-Activity Relationship Surface Tertiary Protein Structure Time Tubular formation Vacuole Work Yeasts asexual base drug development in vivo insight intrahepatic knock-down knockout gene mRNA Expression malformation new therapeutic target novel parasitism protein transport residence resistance mechanism small molecule solute spatiotemporal trafficking

项目摘要

ABSTRACT The endoplasmic reticulum (ER) of eukaryotic cells is an essential organelle with many critical functions including, protein secretion. Its function is closely tied to its morphology. Work in higher eukaryotes has shown that mutations in key proteins required to generate the ER tubular network cause specific growth and developmental defects. In contrast to higher eukaryotes, little is known of how the ER is shaped in early eukaryotes such as protozoa. ER structure in the protozoan parasite, Plasmodium is dynamic and stage-specific but its molecular determinants are unknown. To understand how the ER acquires its shape in different stages of Plasmodium, we identified homologs of key ER-shaping proteins including ones that contain a reticulon homology domain. One of these protein induces membrane curvature in vitro. P. berghei parasites lacking the protein have dysmorphic ER, an enlarged digestive vacuole, are severely attenuated in the asexual cycle but infect hepatocytes normally. We hypothesize that the putative Plasmodium ER-shaping proteins we identified have stage-specific roles in maintaining proper ER structure/function. This proposal will determine the contributions of these proteins in shaping the ER of erythrocytic and hepatic stages of Plasmodium, using morphological and ultrastructural studies of P. berghei gene-knockouts. It will determine the effect of their loss on a key ER function, protein trafficking in the parasite. Our study will provide the first causal link between ER architecture, protein trafficking and the ability of the malaria parasite to reside in different host environments.

抽象的真核细胞的内质网（ER）是具有许多关键功能的重要细胞器包括蛋白质分泌。其功能与其形态密切相关。高等真核生物的工作表明生成 ER 管状网络所需的关键蛋白质的突变会导致特定的生长和发育缺陷。与高等真核生物相比，人们对 ER 在早期是如何形成的知之甚少。真核生物，例如原生动物。原生动物寄生虫中的 ER 结构，疟原虫是动态的且具有阶段特异性，但其分子决定因素未知。为了了解内质网如何在疟原虫的不同阶段形成其形状，我们鉴定了关键 ER 塑造蛋白的同源物，包括含有网状同源结构域的蛋白。其中一种蛋白质可在体外诱导膜弯曲。缺乏这种蛋白质的伯氏疟原虫寄生虫畸形 ER（一种扩大的消化液泡）在无性周期中严重减弱，但会感染肝细胞正常。我们假设我们鉴定出的推定疟原虫内质网塑造蛋白具有在维持适当的 ER 结构/功能中的阶段特定作用。该提案将确定捐款使用形态学和方法研究这些蛋白质在塑造疟原虫红细胞和肝脏阶段的 ER 伯氏疟原虫基因敲除的超微结构研究。它将决定他们的损失对关键 ER 的影响功能，寄生虫中的蛋白质运输。我们的研究将提供 ER 架构之间的第一个因果关系，蛋白质贩运和疟疾寄生虫在不同宿主环境中生存的能力。