Leishmaniasis treatment: Macrophage scavenger receptor

利什曼病治疗：巨噬细胞清道夫受体

基本信息

批准号：
7446196
负责人：
ROBERT O'Mara RYAN
金额：
$ 36.89万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7446196
关键词：
Adverse effects AmBisome Amino Acids Amphotericin B Amphotericin B Liposomal Antibiotics Apolipoproteins Binding Cells Characteristics Charge Chemicals Chinese Hamster Ovary Cell Complex Confocal Microscopy Country Dendritic Cells Disease Dose Drug Delivery Systems Drug Formulations Drug Kinetics Drug or chemical Tissue Distribution Engineering Family Genetic Engineering Goals Growth Hepatic Human Immune response In Vitro Inbred BALB C Mice Individual Infection Kidney Kinetics Langerhans cell Leishmania Leishmania major Leishmaniasis Lesion Ligands Lipids Liposomes Localized Measures Mediating Micelles Miltefosine Modification Molecular Monitor Mouse Strains Mus Mutation Nature Parasites Parasitic Diseases Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phospholipids Plasma Polyenes Positioning Attribute Preparation Property Proteins Protozoa Recombinants Research Research Personnel Resistance SR-A proteins Shapes Site Site-Directed Mutagenesis Structure T-Lymphocyte Technology Testing Therapeutic Index Tissues Toxic effect Treatment Protocols Vesicle amphotericin B-deoxycholate base cell type concept cytokine design in vivo insight macrophage macrophage scavenger receptors member mouse model nanoscale novel particle receptor research study response size targeted delivery time interval

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our research is to apply the unique structural features and lipid interaction properties of apolipoproteins to the treatment of leishmaniasis. Apolipoproteins possess the capacity to transform phospholipid vesicles into discrete, nanometer scale, disc-shaped, complexes termed nanodisks (ND). Studies to date have shown that incorporation of specific hydrophobic drug molecules into ND is feasible. ND loaded with the polyene antibiotic amphotericin B (ampB) effectively inhibits fungal growth in vitro. Furthermore, in vivo experiments in Leishmania major infected mice have revealed that ampB-ND show efficacy at non-toxic doses. To investigate the molecular basis of this effect, pharmacokinetic studies will be performed to determine plasma decay kinetics and tissue distribution of ampB administered as ND. The apolipoprotein component of ND will be subject to chemical and/or genetic alteration to create a molecule that is recognized by the class A scavenger receptor (SR-A) on macrophages. Site-directed mutagenesis of the apolipoprotein component of ND will be performed to remove specific positively charged residues and position negatively charged amino acid residues such that they create a recognition site for SR-A. Chinese hamster ovary cells transfected with SR-A will be employed in binding experiments designed to measure the SR-A binding activity of engineered apolipoproteins. The efficacy of ampB-ND harboring apolipoprotein components targeted to SR-A will be evaluated in a mouse model of leishmaniasis. Studies will be performed to examine the potential enhancement achieved by incorporating ampB with a second hydrophobic anti-leishmanial drug, hexadecylphosphocholine, into ND. The extent to which ampB-ND induce parasite destruction in cells that harbor L. major will be assessed and the effect of ampB-ND exposure on the T cell/cytokine response of human peripheral blood mononuclear cells determined. The results of these experiments should offer new opportunity for the treatment of leishmaniasis, provide further insight into the ligand recognition characteristics of SR-A, and document the utility of ND as vehicles for targeted delivery of hydrophobic drugs.

描述（由申请人提供）：我们研究的长期目标是将载脂蛋白的独特结构特征和脂质相互作用应用于利什曼病的治疗。载脂蛋白具有将磷脂囊泡转化为离散的，纳米尺度，圆盘形的，称为纳米虫（ND）的能力。迄今为止的研究表明，将特定的疏水性药物分子掺入ND是可行的。 ND用多烯抗生素两性霉素B（AMPB）有效地抑制了真菌的体外生长。此外，利什曼原虫主要感染小鼠的体内实验表明，AMPB-ND在无毒剂量时表现出疗效。为了研究这种作用的分子基础，将进行药代动力学研究，以确定施用的AMPB的血浆衰减动力学和组织分布。 ND的载脂蛋白成分将受到化学和/或遗传改变的约束，以创建一个在巨噬细胞上被A级清道夫受体（SR-A）识别的分子。将执行ND的载脂蛋白成分的位置定向诱变，以去除特定带电的残基和负电荷的氨基酸残基的位置，从而为SR-A创建识别位点。用SR-A转染的中国仓鼠卵巢细胞将用于旨在测量工程载脂蛋白的SR-A结合活性的结合实验中。将在利什曼病的小鼠模型中评估携带针对SR-A的载脂蛋白成分的AMPB-ND的功效。将进行研究，以检查通过将AMPB与第二种疏水性抗lesiishManial药物六二烷基磷酸胆碱合并到ND中，从而实现了潜在的增强。 AMPB-ND在多大程度上诱导携带L的细胞中的寄生虫破坏，以及AMPB-ND暴露对人外周血单核细胞的T细胞/细胞因子反应的影响。这些实验的结果应该为治疗利什曼病的治疗提供新的机会，进一步了解SR-A的配体识别特征，并记录ND作为目标递送疏水药物的载体。