Role of Inflammation and Oxidative Stress in Parkinson's Disease

衰老与帕金森病（PD）衰老是PD的主要危险因素。尽管报道成功 与神经营养或神经保护治疗药物或细胞替代疗法在动物模型 PD，没有导致临床有效的治疗途径，治愈疾病复杂的各个方面。 由于衰老是帕金森病的头号危险因素，因此在设计合适的动物时必须考虑到这一点 模型本文提出的研究是独特的，因为我们利用衰老作为一个重要方面， 我们的模型，许多研究表明，老化的“环境”可能是一个关键因素， 对治疗的反应。 炎症和帕金森病。大脑中的炎症，特别是小胶质细胞的激活 已经越来越多地与PD的持续发病机制相关，以及其他几种 神经退行性疾病一个尚未被广泛考虑的领域是先天免疫功能 受到老化的深刻影响。我们已经证明了蛋白质组谱的深刻变化 小胶质细胞与年龄的关系，其他人也研究了基因组的变化。我们最近展示了 一些在年轻动物中成功治疗PD模型的抗炎方法， 对老年动物有效。指出衰老作为一个与疾病有关的因素的重要作用 进展和对治疗剂的反应。 外泌体是炎症的强大基因组调节剂：人类脂肪源性干细胞 (hASC的）表现出能够调节宿主环境的分泌蛋白组。其中， 分子，被称为外泌体的小膜结合囊泡可以调节免疫功能，作为其功能的一部分。 脑损伤和癫痫后的作用机制。外泌体含有长链非编码RNA（lncRNA） 作为基因组调节剂。外泌体是递送神经保护剂的理想载体，因为 与未封装的RNA相比，它们具有独特的磨练组织的能力，以及更高的稳定性。此外，本发明还 我们有证据表明，它们在基因组水平上调节炎症，这使它们成为一个强大的工具， 作为PD的治疗药物 衰老影响小胶质细胞表型，降低某些治疗的疗效。我们的假设是 hASC外来体通过递送与转移相关的lncRNA在基因组水平上改变小胶质细胞功能 肺腺癌转录本1（MALAT 1）和其他重要因子，因此使其成为用于 老年受试者我们将通过分离年轻和老年大鼠的小胶质细胞来探索这一点， 鼻内hASC外泌体并进行基于先进质谱的表型分析。我们将 在年轻人中的PD的AAV 9-α-突触核蛋白模型的进展期间表征小胶质细胞蛋白质组学谱 老年老鼠 我们假设，hASDCexo将调节PD病理的进展，通过相互作用， 先天免疫系统在基因组水平。许多治疗方法集中在改变先天性 免疫功能已经成功地减少了来自α-突触核蛋白病理学，包括我们对 CX3CL1。我们假设hASCexo通过调节小胶质细胞基因， 表情我们将在PD的AAV 9-Syn模型中使用hASCexo的鼻内递送来检查这一点。我们 进一步预测外泌体在老年大鼠中调节PD病理学进展的保留功效。

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.