Role of Inflammation and Oxidative Stress in Parkinson's Disease

炎症和氧化应激在帕金森病中的作用

• 批准号: 9887131
• 负责人: PAULA C BICKFORD
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887131
• 关键词: Adipose tissue; Age; Aging; Animal Model; Animals; Anti-Inflammatory Agents; Area; Biological Process; Brain; Brain Injuries; CX3CL1 gene; Cell Line; Cell Survival; Cells; Clinical; Complex; DNA Sequence Alteration; Data; Disease; Disease Progression; Disease model; Dopaminergic Cell; Encapsulated; Environment; Epilepsy; Exposure to; Gene Expression; Genomics; Home environment; Human; Hydroxydopamines; Immune; Immunoprecipitation; Inflammation; Innate Immune System; MALAT1 gene; Mass Spectrum Analysis; Mediating; Membrane; Microglia; Mitochondria; Modeling; Molecular; Natural regeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuroprotective Agents; Onset of illness; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Phagocytosis; Pharmaceutical Preparations; Phenotype; Proteins; Proteomics; Publishing; RNA; Rattus; Replacement Therapy; Reporting; Risk Factors; Role; Therapeutic; Tissues; Toxic effect; Untranslated RNA; Vesicle; aged; alpha synuclein; base; cell age; cell motility; cell transformation; design; effective therapy; exosome; immune function; improved; innate immune function; juvenile animal; microchip; resilience; response; stem cells; success; tool; transcriptomics; vector

Aging and Parkinson's disease (PD). Aging is the primary risk factor for PD. Despite reported success with neurotrophic or neuroprotective therapeutic drugs or cell replacement therapies in animal models of PD, none have led to a clinically effective treatment avenue, curing all aspects of the disease complex. Since aging is the number one risk factor for PD, it must be considered in designing appropriate animal models. The studies proposed herein are unique in that we utilize aging as an important aspect of our models, many studies have shown that the aged “environment” may be a critical factor in response to therapeutics. Inflammation and Parkinson’s disease. Inflammation in the brain, in particular, activation of microglia has been increasingly associated with the ongoing pathogenesis of PD, as well as several other neurodegenerative disorders. An area that has not been widely considered is that innate immune function is profoundly impacted by aging. We have demonstrated profound changes in proteomic profiles of microglia with age, and others have examined genomic alterations as well. We have recently demonstrated that some anti-inflammatory approaches to treat PD models that are successful in young animals, are not as efficacious in aged animals. Pointing to an important role of aging as a factor involved in disease progression and the response to therapeutics. Exosomes are powerful genomic modulators of inflammation: Human adipose-derived stem cells (hASC’s) manifest a secretome that is capable of modulating the environment of the host. Among these secreted molecules, small membrane-bound vesicles known as exosomes can modulate immune function as part of their mechanism of action following both brain injury and epilepsy. Exosomes contain long non coding RNA (lncRNA) that act as genomic modulators. Exosomes are an ideal vector for delivery of neuroprotective agents because of their unique ability to hone to tissues, and their increased stability compared to un-encapsulated RNA. Further, we have evidence that they modulate inflammation at the genomic level, making them a powerful tool to explore as a therapeutic in PD Aging impacts microglial phenotype, reducing the efficacy some therapeutics. It is our hypothesis, that hASC exosomes alter microglial function at a genomic level by delivery of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1), and other important factors, thus making them ideal for use in aged subjects. We will explore this by isolating microglia from young and aged rats, treated with and without intranasal hASC exosomes and perform advanced mass spectrometry based phenotypic profiling. We will characterize microglia proteomic profiles during progression of an AAV9-a-synuclein model of PD in young and aged rats. We hypothesize that hASDCexo will modulate the progression of PD pathology by interacting with the innate immune system at the genomic level. Many therapeutic approaches focused on altering innate immune function have been successful in reducing pathology from a-synuclein, including our studies with CX3CL1. We hypothesize that hASCexo will reduce PD pathology by a modulating microglial gene expression. We will examine this using intranasal delivery of hASCexo in an AAV9-Syn model of PD. We further predict retained efficacy of exosomes in aged rats in modulating progression of PD pathology.

衰老与帕金森病（PD）。衰老是帕金森病的主要危险因素。尽管报道成功