Relationship between nigrostriatal DA depletion and insulin resistance

描述(由申请人提供)：临床研究表明帕金森氏病(PD)和2型糖尿病(T2D)之间存在相关性。我们建议对这些疾病之间的关系进行临床前调查。该项目的长期目标有两个：确定这些疾病是如何机械地联系在一起的，并调查可能的治疗干预措施。我们的第一个目标是研究帕金森病是T2D的危险因素。我们将向黑质纹状体通路注入6-羟基多巴胺，并分析多巴胺耗竭对大脑和外周胰岛素信号的影响。在我们的第二个实验目标中，我们将使用胰岛素抵抗模型(高脂饮食)来分析糖尿病在帕金森病发生中可能起作用的机制。高血糖和高胰岛素水平已被证明会影响大脑中的多巴胺功能。我们将分析胰岛素抵抗和高胰岛素血症对脑内胰岛素信号、基底节DA功能和神经氧化应激水平的影响。我们的最终目标是调查胰岛素抵抗是否会在部分损伤模型中加剧多巴胺能退化，以及药物干预是否可以缓解这种影响。这一点很重要，因为导致氧化损伤的环境因素，如杀虫剂，已被证明增加了患帕金森病的可能性。确定环境暴露于氧化剂的影响是否会因胰岛素抵抗而加剧，这一点很重要。确定这些疾病是如何联系在一起的，是破坏这种关系并降低患有PD或T2D的个体后来同时患上这两种疾病的可能性的第一步。此外，我们还将提供对每种特定疾病的病理机制的更大洞察力。与公众健康相关：许多帕金森患者存在糖耐量异常，L-多巴治疗可能会加剧这种情况，并增加治疗的副作用，如骨骼发育不良。此外，最近的一项临床研究发现，患有T2D的人患PD的可能性比非糖尿病患者高83%，这表明T2D可能是PD的危险因素。T2D和PD之间的机械性关联值得关注。如果不能解决这一迫在眉睫的临床问题，可能会导致每种疾病的发病率增加，疾病严重程度增加，治疗效果降低。

DESCRIPTION (provided by applicant): Clinical studies have shown a correlation between Parkinson's disease (PD) and Type 2 Diabetes (T2D). We propose a preclinical investigation of relationship between these diseases. The long term objective of this project is twofold: to determine how these diseases are linked mechanistically and to investigate possible therapeutic interventions. Our first aim is to investigate PD as a risk factor for T2D. We will inject 6-hydroxydopamine into the nigrostriatal pathway and analyze the effect of dopamine depletion on insulin signaling in the brain and periphery. In our second experimental aim, we will use a model of insulin resistance (high fat diet) to analyze mechanisms by which diabetes mellitus may play a role in development of PD. High blood glucose and insulin levels have been shown to affect dopamine function in the brain. We will analyze the effects of insulin resistance and hyperinsulinemia on brain insulin signaling, DA function in the basal ganglia, and neural oxidative stress levels. Our final aim will investigate whether insulin resistance exacerbates dopaminergic degeneration in a partial lesion model, and whether a pharmacological intervention can alleviate this effect. This is important because environmental factors that cause oxidative damage, such as pesticides, have been shown to increase the likelihood of developing PD. It is important to determine whether the effects of environmental exposure to oxidants could be compounded by insulin resistance. Determining how these diseases are linked is the first step in disrupting this relationship and decreasing the likelihood that an individual who suffers from either PD or T2D will later develop both diseases. In addition, we will also provide greater mechanistic insight into the pathologies mediating each specific disease. Relevance to public health: Many Parkinson's patients have abnormal glucose tolerance, which may be exacerbated by L-DOPA therapy and increase side effects of therapy such as dyskenesias. In addition, a recent clinical study has found individuals with T2D to be 83% more likely to develop PD than their non-diabetic counterparts, indicating T2D as a possible risk factor for PD. A mechanistic association between T2D and PD demands attention. Failure to address this looming clinical issue could result in increased incidence of each disease, increased disease severity, and decreased therapeutic effectiveness.