Immunotherapy for Synucleinopathies: Can Gut Microbiota Affect Efficacy?

突触核蛋白病的免疫疗法：肠道微生物群会影响疗效吗？

• 批准号: 10666872
• 负责人: VOLKER MAI
• 金额: $ 41.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666872
• 关键词: Address; Adjuvant; Adoptive Transfer; Affect; Animal Model; Animals; Bacteria; Basal Ganglia; Bifidobacterium; Biological Assay; Brain Pathology; Brain Stem; CD8-Positive T-Lymphocytes; Cells; Cellular immunotherapy; Clinical Trials; Data; Deposition; Disabled Persons; Disease; Disease Progression; Dyskinetic syndrome; Effectiveness; Flow Cytometry; Functional disorder; Future; Genetic Transcription; Heterozygote; Immune; Immune System Diseases; Immune response; Immunity; Immunohistochemistry; Immunologic Markers; Immunology procedure; Immunotherapy; In Vitro; Injections; Interferon Type II; Interleukin-10; Interleukin-5; Intestines; Intramuscular; Lewy Bodies; Lewy Body Dementia; Malignant Neoplasms; Medical; Messenger RNA; Methods; Midbrain structure; Modeling; Modification; Motor; Motor Neurons; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Onset of illness; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenocopy; Phenotype; Play; Pre-Clinical Model; Protocols documentation; Publishing; Research; Ribosomal DNA; Role; Sampling; Symptoms; T cell response; T-Lymphocyte; Technology; Therapeutic; Time; Transgenic Mice; Work; alpha synuclein; antigen-specific T cells; behavior measurement; chemokine; cohort; commensal microbes; cytokine; dopamine replacement therapy; dopaminergic neuron; dysbiosis; efficacy evaluation; fecal transplantation; gut homeostasis; gut microbiota; immune function; immunomodulatory therapies; immunoregulation; improved; innovation; microbial; microbiota; motor symptom; mouse model; nervous system disorder; neuroinflammation; neuron loss; novel; peripheral blood; pre-formed fibril; response; side effect; standard care; symptomatic improvement; synucleinopathy; translational potential

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.

项目概要 路易体痴呆 (LBD) 和帕金森病 (PD) 的病理特征是存在 路易体由错误折叠的 α 突触核蛋白 (α-syn) 内含物组成，这些疾病是进行性的，并且 多巴胺能神经元在多个运动和非运动基底神经节回路中退化的结果。 虽然目前治疗帕金森病的黄金标准是多巴胺替代疗法，但它仅针对运动神经元 症状，并随着时间的推移导致运动波动和运动障碍，因此存在未满足的需求。 在 LBD 和 PD 等不可抗拒的疾病发作后提供可行的治疗。 建议，我们将通过一种独特的免疫调节方法来靶向 α-syn 沉积和神经死亡 目标 1 中病理学开始后两个不同时间点的动物模型，并评估免疫标志物 参与目标 2 中的 ACT。有证据表明微生物失调会影响宿主免疫 功能，并且肠道微生物群可能在多种癌症的免疫治疗效果中发挥作用。 因此，我们还将评估宿主免疫和微生物群之间是否存在串扰。 病理学开始后 ACT 对肠道微生物群的影响，以及微生物群是否在我们的功效中发挥作用 目标 3 中的免疫疗法。最终，这项创新研究的结果将为应用铺平道路 路易体痴呆和其他突触核蛋白病的免疫调节疗法并提供共生疗法 微生物群作为治疗佐剂。