Immunotherapy for Synucleinopathies: Can Gut Microbiota Affect Efficacy?

项目摘要 路易体痴呆症（LBD）和帕金森病（PD）的病理特征在于存在 路易体，由错误折叠的α-突触核蛋白（α-syn）内含物组成。这些疾病是渐进的， 是由多个运动和非运动基底神经节回路中的多巴胺能神经元变性引起的。 虽然目前帕金森病的金标准治疗是多巴胺替代疗法，但它只针对运动神经元， 症状，并随着时间的推移导致运动波动和运动障碍。因此，有一个未满足的需要， 在诸如LBD和PD的突触蛋白病的不可抵抗的疾病发作后提供可行的治疗。在这 我们将通过一种独特的免疫调节方法靶向α-syn沉积和神经元死亡， 在目标1中病理学开始后的两个不同时间点建立动物模型，并评估免疫标志物 参与Aim 2中的ACT。有证据表明，微生物生态失调可以影响宿主免疫 肠道微生物群可能在几种癌症的免疫治疗功效中发挥作用。这表明 宿主免疫力和微生物群之间存在串扰。因此，我们亦会评估有否影响 ACT对肠道微生物群的影响，以及微生物群是否在我们的治疗效果中发挥作用。 免疫治疗的目的3.最终，这项创新和新颖的研究结果将为应用 路易体痴呆和其他突触核蛋白病的免疫调节治疗以及 微生物群作为治疗佐剂。

PROJECT SUMMARY Lewy Body Dementia (LBD) and Parkinson's disease (PD) are pathologically characterized by the presence of Lewy bodies, composed of misfolded alpha synuclein (α-syn) inclusions. These disorders are progressive, and result from the degeneration of dopaminergic neurons in multiple motor and non-motor basal ganglia circuits. While the current gold standard treatment for PD is dopamine replacement therapy, it only addresses motor symptoms, and over time results in motor fluctuations and dyskinesias. Hence there is an unmet need for delivering viable treatments after inexorable disease onset in syncleinopathies such as LBD and PD. In this proposal, we will target α-syn deposition and neuronal death via a unique, immunomodulatory approach in an animal model at two different time points after initiation of pathology in Aim 1, and assess immune markers involved in ACT in Aim 2. There is evidence suggesting that microbial dysbiosis can influence host immune function and that gut microbiota could play a role in immunotherapy efficacy in several cancers. This demonstrates the existence of a crosstalk between host immunity and microbiota. Hence, we will also assess if there is an impact of ACT on gut microbiota after pathology has initiated, and whether microbiota play a role in efficacy of our immunotherapy in Aim 3. Ultimately, findings from this innovative and novel study will pave the way for applying immunomodulatory therapies in Lewy body dementias and other synucleinopathies and delivering commensal microbiota as therapeutic adjuvants.