Receptors for Neuron and Glia Survival in Chagas Disease

恰加斯病中神经元和神经胶质细胞存活的受体

• 批准号: 6622066
• 负责人: Mercio A Perrin
• 金额: $ 33.88万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-15 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622066
• 关键词: PC12 cells; Schwann cells; Trypanosoma cruzi; affinity chromatography; astrocytes; enzyme activity; enzyme mechanism; exo alpha sialidase; expression cloning; host organism interaction; nervous system regeneration; nuclear factor kappa beta; phosphorylation; protein engineering; receptor expression; trypanosomiasis

Patients with Chagas' disease, caused by the protozoan Trypanosoma cruzi, exhibit an acute stage, characterized by robust parasite growth and neural degeneration; an asymptomatic indeterminate chronic phase, marked by the regeneration of neurons; and a chronic phase, designated by immunological alterations and tremendous degeneration of neurons. Most patients remain in the indeterminate phase for years or decades. Some asymptomatic patients progress to the chronic, fatal chronic disease stage. It remains a mystery why patients can remain asymptomatic and with signs of neural regeneration for life while others develop neuro-degeneration. Recent studies demonstrate that the trans-sialidase (TS) of T. cruzi is a potent survival factor for several types of neurons, and for glial Schwann cells and astrocytes. TS can be as good as nerve growth factor (NGF) in protecting sympathetic-like PC12 cells against apoptosis provoked by starvation. In addition, TS synergizes with cytokines of the interleukin-6 family to protect neurons. Likewise, TS is as good as neureglin and other growth factors that promote survival of glial Schwann cells. Yet, TS has no detectable homology to NGF and other neutrophins, and to cytokine neurotrophic factors. Thus, it remains unknown how TS promotes survival of neurons and glial cells. The best way to understand T. cruzi-induced survival is to know the nature of the receptors TS react with on neurons and glial cells. This project attempts to identify TS receptors that T. cruzi uses to promote cell survival during invasion of the nervous system. The project will utilize a state-or-the-art combination of cell biology, biochemistry, genetics, and immunochemical approaches to identify and characterize relevant receptors. The outcome of the studies could very well provide insights into the pathogenesis of Chagas' disease and to lead to the development of compounds to treat not only Chagas' disease but also other neurodegenerative disorders.

由原生动物克氏锥虫引起的恰加斯病患者表现出急性期，其特征是寄生虫生长旺盛和神经变性；无症状的不确定慢性期，以神经元再生为标志；和慢性阶段，以免疫改变和神经元的巨大退化为特征。 大多数患者仍处于不确定阶段数年或数十年。一些无症状的患者进展到慢性、致命的慢性病阶段。 为什么患者可以终生保持无症状且具有神经再生迹象，而其他人则出现神经退行性变，这仍然是一个谜。最近的研究表明，克氏锥虫的转唾液酸酶 (TS) 是多种类型神经元、神经胶质雪旺细胞和星形胶质细胞的有效生存因子。 TS 可以与神经生长因子 (NGF) 一样有效地保护类交感神经 PC12 细胞免受饥饿引起的细胞凋亡。 此外，TS 与 IL-6 家族细胞因子协同作用，保护神经元。 同样，TS 与神经调节蛋白和其他促进神经胶质雪旺细胞存活的生长因子一样有效。 然而，TS 与 NGF 和其他中性粒细胞以及细胞因子神经营养因子没有可检测到的同源性。 因此，TS 如何促进神经元和神经胶质细胞的存活仍不清楚。了解克氏锥虫诱导的生存的最佳方法是了解 TS 与神经元和神经胶质细胞反应的受体的性质。 该项目试图鉴定克氏锥虫在入侵神经系统期间用来促进细胞存活的 TS 受体。 该项目将利用细胞生物学、生物化学、遗传学和免疫化学方法的最先进组合来识别和表征相关受体。 研究结果很可能为了解恰加斯病的发病机制提供深入见解，并导致开发出不仅可以治疗恰加斯病而且可以治疗其他神经退行性疾病的化合物。