Choroid Plexus as a Target in Metal-induced Neurotoxicity

 描述(申请人提供)：选择性脑区神经元丢失是帕金森病(PD)和阿尔茨海默病(AD)等神经退行性疾病的病理特征。最近的研究提供了证据表明，成人大脑中确实发生了神经再生，并可能通过维持帕金森病患者的非运动功能和减缓AD患者的认知退化和记忆丧失来减轻成人神经元的损失。在成体神经发生过程中，新的神经元从一个被称为脑室下区(SVZ)的增殖壁龛中产生，它由脑室中的脑脊液(CSF)滋养。SVZ通过吻端迁移流(RMS)向嗅球(OB)和其他脑区提供神经干细胞/增殖细胞(NSPC)。在上一次资助期间(2009-2014)，我们发现：(I)与成年大鼠的其他脑区相比，SVZ中的铜含量非常高；(Ii)暴露于锰(Mn)会降低SVZ中的铜水平；以及(Iii)产生脑脊液的脉络丛(CP)促进了SVZ中NSPC的增殖和分化。在这一竞争更新中需要检验的中心假说是，铜在调节SVZ的神经发生中起着关键作用；暴露于锰并随后在CP中积累，扰乱了CP、CSF和SVZ中的铜的动态平衡，导致成人大脑中的神经发生受阻。在目标1中，我们将建立体内锰暴露对神经发生的剂量-时间-反应关系。目标2的研究将揭示铜在SVZ中高度积累的机制，并将确定是否存在一个阈值水平，超过或低于该阈值，铜对干细胞增殖、迁移和分化的调控将因锰暴露而受到影响。此外，Aim 3实验将集中于锰吸入暴露如何追溯损害OB和SVZ神经发生的终点毒性。最后，在目的4中，我们将探索在SVZ内CP分泌的对神经发生有直接影响的因素，以期建立成人神经发生中CP-CSF-SVZ轴的新概念。这一建议延续了我们的长期研究目标，即探索CP及其邻近的脑结构在金属诱导的神经毒性中的作用。本申请中提出的研究将建立一个新的研究领域，即成人神经发生的毒理学意义；将探索锰诱导的帕金森病的新机制；并将确定CP和SVZ在成人神经发生中的新关系。这些结果将对我们理解脑部疾病的病因学产生深远的影响。

 DESCRIPTION (provided by applicant): Loss of neurons in selective brain regions is the pathological characteristic of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer's disease (AD). Recent studies have provided evidence that neurogenesis in adult brain does occur and may mitigate adult neuronal loss by sustaining non‐motor function in PD and slowing cognitive deterioration and memory loss in AD. During adult neurogenesis, new neurons are generated from a proliferative niche called the subventricular zone (SVZ), which is nurtured by the cerebrospinal fluid (CSF) in brain ventricles. The SVZ provides neural stem/proliferating cells (NSPC) via the rostral migration stream (RMS) to the olfactory bulb (OB) and other brain regions. During the last funded period (2009‐2014), we have discovered that (i) the SVZ contains extraordinarily high amounts of copper (Cu) compared to other brain regions in adult rats; (ii) exposure to manganese (Mn) decreases Cu levels in SVZ; and (iii) the choroid plexus (CP), which produces the CSF, facilitates NSPC's proliferation and differentiation in SVZ. The central hypothesis to be tested in this competing renewal is that Cu plays a critical role in regulating neurogenesis in the SVZ; Mn exposure and subsequent accumulation in the CP disturbs Cu homeostasis in the CP, CSF and SVZ, leading to an arrested neurogenesis in adult brain. In Aim 1, we will establish the dose‐time‐response relationship of in vivo Mn exposure on neurogenesis. Studies in Aim 2 will reveal the mechanism of the high Cu accumulation in the SVZ and will determine if there is a threshold level above or below which Cu's modulation of stem cell's proliferation, migration and differentiation becomes compromised by Mn exposure. Furthermore, the Aim 3 experiments will focus on the endpoint toxicity of how Mn inhalation exposure retrospectively damages neurogenesis in the OB and SVZ. Finally in Aim 4, we will explore the factors secreted by the CP that have the direct effect on neurogenesis in the SVZ in the hope to establish a novel concept of the CP‐CSF‐SVZ axis in adult neurogenesis. This proposal continues our long‐term research goal, i.e., to explore the role of the CP and adjacent brain structures in metal‐induced neurotoxicities. Studies proposed in this application will establish a novel research area, i.e., toxicological implications of adult neurogenesis; will explore a novel mechanism of Mn‐induced parkinsonian disorder; and will define a novel relationship between CP and SVZ in adult neurogenesis. The outcomes will have a profound impact on our understanding of etiology of brain diseases.