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Investigating the Cytsolic Heme Pool in P. falciparum

研究恶性疟原虫胞质血红素池

基本信息

批准号：
7061345
负责人：
JACQUIN C NILES
金额：
$ 5.4万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2007-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7061345
关键词：
Plasmodium falciparum SDS polyacrylamide gel electrophoresis chloroquine cytoplasm drug resistance heme host organism interaction malaria oligonucleotides pathologic process peptide library polymerase chain reaction postdoctoral investigator protein binding protein degradation protein structure function

项目摘要

DESCRIPTION (provided by applicant): During malarial infection by Plasmodium falciparum, significant, amounts of hemoglobin are degraded by the intraerythrocytic parasite in a specialized food vacuole. The released amino acids are utilized to support growth, but heme is mostly detoxified to hemozoin in the food vacuole. However, it is unclear how much heme partitions to the parasite's cytosol, and the role it plays in parasite physiology. Furthermore, chloroquine, a commonly used anti-malarial drug has been suggested to increase cytosolic heme flux, but this has not been proven. We will address these issues by using a functional approach rather than mass balance measurements that are prone to large errors in biological systems. Our goals are to (1) develop high affinity RNA aptamers to heme using SELEX, and, (2) introduce them into P. falciparum, and determine their impact on parasite survival in the presence and absence of chloroquine. The aptamers are expected to be cytosolic given their negative charge, and should not interfere with heme polymerization in the food vacuole, thus providing a tool to selectively investigate the heme pool in the cytosol. These studies are important to advance our understanding of how P. falciparum disposes and/or utilizes host-derived heme, and to specifically investigate a potential mechanism by which the commonly used anti-malarial drugs exert their toxicity. Resistance to chloroquine is becoming increasingly widespread, and occurs via efflux mechanisms that prevent drug accumulation within the parasite. If parasite survival is intricately associated with the status of a physiologic cytosolic heme pool, this may represent another drug development target that circumvents the known resistance mechanism.

描述（由申请人提供）：在恶性疟原虫感染疟疾期间，红细胞内寄生虫在特定的食物液泡中降解大量的血红蛋白。释放的氨基酸被用来支持生长，但血红素在食物液泡中主要被解毒为血色素。然而，目前尚不清楚有多少血红素被分割到寄生虫的细胞质中，以及它在寄生虫生理学中所起的作用。此外，一种常用的抗疟疾药物氯喹被认为可以增加细胞质血红素通量，但这尚未得到证实。我们将通过使用功能方法来解决这些问题，而不是在生物系统中容易产生大误差的质量平衡测量。我们的目标是：(1)利用SELEX开发血红素高亲和力RNA适配体，(2)将它们引入恶性疟原虫，并确定它们在存在和不存在氯喹的情况下对寄生虫存活的影响。鉴于其负电荷，该适体预计是细胞质的，并且不应干扰食物液泡中的血红素聚合，从而提供了一种选择性研究细胞质中血红素池的工具。这些研究对于提高我们对恶性疟原虫如何处理和/或利用宿主来源的血红素的理解，以及专门研究常用抗疟疾药物发挥其毒性的潜在机制具有重要意义。对氯喹的耐药性正变得越来越普遍，并通过防止药物在寄生虫内积累的外排机制发生。如果寄生虫的生存与生理胞质血红素库的状态复杂相关，这可能代表了另一个绕过已知耐药机制的药物开发靶点。