Trypanosome Lysis by Human Haptoglobin Related Protein

人触珠蛋白相关蛋白裂解锥虫

• 批准号: 7228450
• 负责人: STEPHEN L HAJDUK
• 金额: $ 32.23万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228450
• 关键词: African; African Trypanosomiasis; Animals; Apolipoprotein A-I; Apolipoproteins; Appendix; Binding; Biochemical; Blood; Blood Circulation; Cattle Diseases; Cells; Characteristics; Collaborations; Complementary DNA; Complex; Cytolysis; Development; Disruption; Endocytosis; Epitopes; Gene Family; Genes; Goals; Grant; Haptoglobins; High Density Lipoproteins; Host Defense Mechanism; Human; In Vitro; Infection; Insecta; Iron; Lead; Ligand Binding Domain; Lipid Peroxidation; Lysosomes; Lytic; Mediating; Membrane; Membrane Lipids; Membrane Proteins; Modeling; Modification; Molecular; Mus; Mutagenesis; Parasites; Pathway interactions; Predisposition; Proteins; Reaction; Reagent; Recombinants; Resistance; Serum; Serum Proteins; Study Subject; Surface; Toxic effect; Transfection; Transgenic Mice; Transgenic Organisms; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma brucei rhodesiense; base; haptoglobin-related protein; human HPR protein; human disease; in vivo; killings; member; mouse model; nagana; novel strategies; receptor; research study; trafficking; uptake

DESCRIPTION (provided by the applicant): Trypanosoma brucei brucei causes the bovine disease Nagana but is non-infectious to humans because of its susceptibility to the cytolytic activity of normal human serum. This activity is due to human haptoglobin related protein (HPR). HPR is found in human sera either as an HDL associated apolipoprotein, trypanosome Lytic factor-i (TLF-l), or as a large protein complex termed TLF-2. The cellular pathway of TLF-l mediated lysis of T b. brucei includes receptor mediated binding to the trypanosome surface, endocytosis and lysosomal targeting. TLF-l kills T b. brucei by destabilization of the lysosomal membrane in an iron dependent reaction that leads to lysosome disruption and cell lysis. The human sleeping sickness parasite Trypanosoma brucei rhodesiense is resistant to TLF-mediated lysis. The mechanism of T b. rhodesiense resistance to TLF-l is associated with a reduction in TLF-l uptake and intracellular trafficking. Expression of a single protein, Serum Resistance Associated (SRA) is sufficient to confer resistance to TLF-l in vitro and in vivo. This protein is a 59 kDa membrane protein that is a member of the VSG gene family. SRA expression is restricted to human sleeping sickness trypanosomes and its expression is transcriptionally regulated. In the proposed studies we will continue to investigate the biochemical and molecular mechanism of J-IPR killing of trypanosomes and the mechanism of SRA protection from TLF-l killing in T b. rhodesiense. The specific aims of this proposal are the following: (1) Determine the structural and biochemical requirements for HPR killing of trypanosomes; (2) Develop a transgenic mouse model for human HPR; (3) Determine the cellular and biochemical mechanisms of SRA inhibition of HPR killing of T b. brucei. Our long-term goals remain to explore the possibilities that modification of HPR or its uptake byhuman sleeping sickness trypanosomes may lead to the identification of novel approaches for treatment of this increasingly important human disease based on this potent innate killing factor.

描述（由申请人提供）： 布氏锥虫会导致牛疾病 Nagana，但由于其对正常人血清的细胞溶解活性敏感，因此对人类无感染性。该活性归因于人类触珠蛋白相关蛋白 (HPR)。 HPR 在人类血清中以 HDL 相关载脂蛋白、锥虫裂解因子-i (TLF-1) 或称为 TLF-2 的大型蛋白质复合物的形式存在。 TLF-1介导的T b裂解的细胞途径。布鲁氏菌包括受体介导的与锥虫表面的结合、内吞作用和溶酶体靶向。 TLF-l 杀死 T b． brucei 通过铁依赖性反应破坏溶酶体膜的稳定性，导致溶酶体破坏和细胞裂解。人类昏睡病寄生虫罗得西亚布氏锥虫对 TLF 介导的裂解具有抵抗力。 Tb 的机制罗得西亚人对 TLF-1 的抗性与 TLF-1 摄取和细胞内运输的减少有关。单一蛋白、血清抗性相关蛋白(SRA)的表达足以在体外和体内赋予对TLF-1的抗性。该蛋白是一种 59 kDa 膜蛋白，属于 VSG 基因家族的成员。 SRA 表达仅限于人类昏睡病锥虫，其表达受转录调控。在拟议的研究中，我们将继续研究 J-IPR 杀灭锥虫的生化和分子机制，以及 SRA 保护锥虫免受 TLF-1 杀伤的机制。罗德西亚。该提案的具体目标如下：（1）确定HPR杀灭锥虫的结构和生化要求； (2) 开发人类HPR转基因小鼠模型； (3)确定SRA抑制HPR杀伤T b的细胞和生化机制。布鲁塞伊。 我们的长期目标仍然是探索对 HPR 进行修饰或人类昏睡病锥虫对 HPR 的吸收的可能性，可能会导致基于这种强大的先天杀伤因子来确定治疗这种日益重要的人类疾病的新方法。