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: 6684099
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684099
• 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.

由原生动物锥虫瘤引起的Chagas疾病的患者表现出急性阶段，其特征是稳健的寄生虫生长和神经变性。以神经元再生为特征的无症状不确定的慢性期；和一个慢性阶段，通过免疫学改变和神经元的巨大变性指定。 大多数患者数年或几十年来一直处于不确定阶段。一些无症状的患者进入了慢性致命的慢性病阶段。 为什么患者可以保持无症状并具有生命神经再生的迹象，而其他人则发展神经脱生，这仍然是一个谜。最近的研究表明，T. cruzi的跨硅化酶（TS）是几种类型的神经元的有效生存因子，以及神经胶质schwann细胞和星形胶质细胞的生存因子。 TS可以与神经生长因子（NGF）一样好，以保护类似于交感神经的PC12细胞免受饥饿引起的凋亡。 此外，TS与白介素-6家族的细胞因子协同保护神经元。 同样，TS与神经和其他生长因子一样好，可促进神经胶质雪水细胞的存活。 然而，TS与NGF和其他中性蛋白以及细胞因子神经营养因素没有可检测的同源性。 因此，TS如何促进神经元和神经胶质细胞的存活仍然未知。理解T. cruzi引起的生存的最佳方法是了解受体TS的性质TS与神经元和神经胶质细胞反应。 该项目试图识别T. Cruzi用来促进神经系统入侵细胞存活的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状态或先进的组合来识别和表征相关受体。 研究的结果很可能可以提供对木马疾病发病机理的见解，并导致化合物的发展，不仅治疗chagas疾病，还可以治疗其他神经退行性疾病。