Neuron Survival in Chagas Disease

描述（由申请人提供）：由克氏锥虫感染引起的恰加斯病患者在急性期表现为神经变性，在慢性不确定（无症状）期表现为神经再生，在慢性症状期表现为神经元变性。大多数患者在数年或数十年内仍无症状，并有神经元再生的迹象。一些无症状的患者进展到慢性、致命的慢性疾病阶段。目前尚不清楚为什么患者可以在几十年内保持无症状和神经再生的迹象，而其他人则在晚年出现神经退行性变。最近的研究表明，克氏绦虫表达表面膜结合和寄生虫衍生的模拟神经营养因子（PDNF），以前称为神经氨酸酶/反式唾液酸酶，能有效促进几种类型的神经元、雪旺细胞和星形胶质细胞的存活。在过去的五年中，PDNF通过结合和激活TrkA神经生长因子（NGF）受体酪氨酸激酶来诱导神经元的存活和分化，这是一个主要的和广泛的受众发现。这一独特的结果为了解神经系统微生物入侵者的分子基础开辟了许多有趣的途径，特别是克氏锥虫是否通过PDNF，像真正的宿主生长因子一样，识别其他神经营养因子受体，通过Trks受体触发神经递质限速酶，携带神经营养因子基元，这些基元可以作为合成肽来利用，以逆转神经元和神经胶质损伤。并引发对Trks的自身免疫反应，这可能会激活或抑制受体功能。该项目将结合细胞生物学、生物化学、遗传学和免疫化学方法来鉴定和表征TrkA和其他受体与PDNF和新型Trk自身抗体的相互作用。最有可能的是，拟议研究的结果将提供对恰加斯病发病机制的见解，特别是神经再生，并导致化合物的发展，主要是ngf样肽模拟物，不仅可以治疗恰加斯病，还可以治疗其他神经退行性疾病，如帕金森病。

DESCRIPTION (provided by applicant): Patients with Chagas' disease, caused by Trypanosoma cruzi infection, exhibit neural degeneration in the acute phase, neuroregeneration in the chronic indeterminate (asymptomatic) phase, and degeneration of neurons in the chronic symptomatic phase. Most patients remain asymptomatic and with signs of neuronal regeneration for years or decades. Some asymptomatic patients progress to the chronic, fatal chronic disease stage. It remains unknown why patients can remain asymptomatic and with signs of neural regeneration for decades while others develop neurodegeneration later in life. Recent studies demonstrate that T. cruzi expresses surface membrane-bound and shed parasite-derived mimic of neurotrophic factors (PDNF), formerly known as neuraminidase/trans-sialidase, that potently promotes survival of several types of neurons, Schwann cells, and astrocytes. A major and wide audience-reaching finding in the previous five years was that PDNF induces survival and differentiation of neurons by binding and activating TrkA nerve growth factor (NGF) receptor tyrosine kinase. This unique result opens up many interesting avenues to understand the molecular basis of a microbial invader of the nervous system, specifically whether T. cruzi, via PDNF, like authentic host growth factors, recognizes other neurotrophin receptors, triggers off neurotransmitter rate-limiting enzymes through Trks receptors, bear neurotrophin motifs that can be exploited as synthetic peptides to reverse neuronal and glial damage, and elicit autoimmune responses to Trks that might activate or inhibit receptor function. The project will utilize a combination of cell biology, biochemistry, genetics, and immunochemical approaches to identify and characterize the interaction of TrkA and other receptors with PDNF and the novel Trk autoantibodies. Most likely, the outcome of the proposed studies will provide insights into the pathogenesis of Chagas' disease, particularly neuroregeneration, and lead to the development of compounds, principally NGF-like peptidomimetics, to treat not only Chagas' disease but also other neurodegenerative disorders such as Parkinson's disease.