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？

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要路易身体痴呆（LBD）和帕金森氏病（PD）在病理上以存在为特征路易体，由错误折叠的α突触核蛋白（α-Syn）夹杂物组成。这些疾病是进步的，多巴胺能神经元在多电动机和非运动基底神经节电路中的变性引起的。虽然当前的PD金标准治疗是多巴胺替代疗法，但它仅解决电动机症状和随着时间的流逝会导致运动波动和运动障碍。因此，有未满足的需求在诸如LBD和PD之类的促疾病中发作后，疾病发作后提供可行的治疗方法。在这个提案，我们将通过独特的免疫调节方法靶向α-Syn沉积和神经元死亡在AIM 1中开始病理学后两个不同时间点的动物模型，并评估免疫标记参与AIM 2的ACT。有证据表明微生物营养不良会影响宿主免疫功能和肠道微生物群可以在几种癌症的免疫疗法效率中发挥作用。这证明了宿主免疫和微生物群之间存在串扰。因此，我们还将评估是否有影响病理启动后对肠道菌群的作用，以及菌群是否在我们的效率中起作用 AIM 3中的免疫疗法。最终，这项创新和新颖的研究的发现将为应用铺平道路路易人体内痴呆症和其他突触核疾病的免疫调节疗法并提供共生微生物群作为治疗调节器。