Role of Prokineticin 2 in Metal Neurotoxicity

Prokineticin 2 在金属神经毒性中的作用

• 批准号: 10587599
• 负责人: ARTHI KANTHASAMY
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-25 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587599
• 关键词: Adult; Affect; Agonist; Animal Model; Animals; Anosmia; Astrocytes; Basal Ganglia; Brain region; C57BL/6 Mouse; Cell Nucleus; Cell model; Cells; Chemotactic Factors; Chronic; Corpus striatum structure; Data; Dendroaspis; Disparity; Dose; Environment; Environmental Exposure; Etiology; Exposure to; Functional disorder; Gene Expression; Globus Pallidus; Goals; Health; Heavy Metals; Homologous Gene; Human; Idiopathic Parkinson Disease; Impairment; In Vitro; Industrialization; Kallmann Syndrome; Link; Manganese; Maps; Mediating; Metal exposure; Metals; Modeling; Molecular; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Deficit; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Neuropeptides; Neurotoxins; Occupational; Olfactory dysfunction; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Pattern; Peptides; Phase; Predisposition; Prosencephalon; Recombinants; Reporting; Role; Signal Pathway; Signal Transduction; Source; Stream; Stress; System; Therapeutic; Time; Up-Regulation; Venoms; astrocyte progenitor; cognitive disability; gene therapy; human tissue; in vivo; insight; migration; motor deficit; motor impairment; mouse model; nerve stem cell; neural circuit; neurobehavioral; neurogenesis; neuron loss; neuronal survival; neuroprotection; neuropsychiatry; neurotoxic; neurotoxicity; neurotoxicology; neurotrophic factor; novel; novel therapeutic intervention; olfactory bulb; pharmacologic; protective effect; receptor; receptor expression; release factor; response; subventricular zone; translational approach

Abstract Chronic environmental exposure to neurotoxic concentrations of manganese (Mn) affects the basal ganglia system and has been linked to the etiology of Parkinsonism. Within basal ganglia (BG), Mn primarily accumulates in the globus pallidus and causes neuronal dysfunction in GABAergic neurons, resulting in dysregulation of the BG neural circuitry. Unlike Parkinson’s disease (PD), DAergic nuclei in the SN are not greatly affected by Mn neurotoxicity. Although Mn neurotoxicity manifests as extrapyramidal motor impairments, animal and human neurotoxicity studies indicate that it is also associated with various neuropsychiatric and cognitive disabilities. Several lines of evidence reveal olfactory deficits in humans following both occupational and environmental Mn exposure. Despite evidence linking olfactory dysfunction and BG pathology in Mn neurotoxicity, the underlying neurotoxicological mechanisms remain poorly understood. Recently, we reported that the neuropeptide prokineticin 2 (PK2) is rapidly upregulated in the early stages of DAergic neurotoxicity in a neurotoxin-induced animal model of Parkinsonism, and it participates in a novel compensatory protective response to counteract neurodegeneration by activating pro-survival pathways. We also obtained exciting new data showing a similar biphasic expression pattern for PK2 during Mn-induced neurotoxicity in vitro and in the SN and olfactory bulb (OB) regions, but not the striatum, of Mn-treated animals. Furthermore, our preliminary studies surprisingly identified that pharmacological stimulation of PK2 receptors or recombinant PK2 (rPK2) significantly upregulates the glial-derived neurotrophic factor (GDNF) expression and release in astrocytes both in vitro and in vivo. Additional preliminary results revealed a robust colocalization of PK2 and GDNF in OB. Thus, we hypothesize that disparity in the induction pattern of PK2-GDNF signaling in BG contributes to the differential vulnerability of GABAergic and DAergic neurons to Mn neurotoxicity. Also, Mn-induced impairment in PK2-GDNF signaling affects neurogenesis required for OB function and striatal neuronal survival. To fully establish the role of the PK2-GDNF axis in the BG and olfactory regions during Mn-induced neurotoxic insult, we will systematically pursue the following specific aims: (i) Map differential PK2 expression in BG, OB, subventricular zone (SVZ), and rostral migratory stream (RMS) regions and functionally correlate with neurogenesis, brain region-specific neuronal vulnerability and neurobehavioral deficits in mouse models of chronic Mn neurotoxicity; (ii) determine whether PK2 regulates GDNF levels and characterize the molecular mechanism of PK2 signaling in regulating GDNF in cell and animal models of Mn neurotoxicity; and (iii) evaluate the translational neuroprotective efficacy of novel PK2 receptor agonism and AAV-PK2/GDNF gene therapy in animal models of Mn neurotoxicity. Overall, we predict that our proposed studies will provide novel mechanistic insights into metal-induced BG and olfactory dysfunction and its role in the pathogenesis of environmentally linked Parkinsonism and will offer a novel therapeutic strategy.

抽象的 长期环境暴露于神经毒性浓度的锰 (Mn) 会影响基底神经节 锰主要在基底神经节 (BG) 内积累，并与帕金森病的病因有关。 在苍白球中，引起 GABA 能神经元的神经元功能障碍，导致 与帕金森病 (PD) 不同，BG 神经回路受 Mn 影响不大。 尽管锰的神经毒性表现为锥体外系运动障碍，但动物和人类 神经毒性研究表明，它还与各种神经精神和认知障碍有关。 多项证据表明，职业和环境锰导致人类嗅觉缺陷 尽管有证据表明锰神经毒性与嗅觉功能障碍和 BG 病理有关，但其根本原因是。 神经毒理学机制仍知之甚少，最近，我们报道了神经肽。 前动力蛋白 2 (PK2) 在神经毒素诱导的 DAergic 神经毒性的早期阶段迅速上调 帕金森病动物模型，它参与一种新颖的补偿性保护反应来抵消 我们还获得了令人兴奋的新数据，显示了类似的结果。 锰诱导的体外神经毒性以及 SN 和嗅球中 PK2 的双相表达模式 经锰处理的动物的（OB）区域，但不是纹状体。此外，我们的初步研究令人惊讶。 确定 PK2 受体或重组 PK2 (rPK2) 的药理学刺激显着上调 体外和体内星形胶质细胞中胶质源性神经营养因子（GDNF）的表达和释放。 其他初步结果揭示了 OB 中 PK2 和 GDNF 的稳健共定位。 BG 中 PK2-GDNF 信号传导诱导模式的差异导致了不同脆弱性 GABA 能和 DA 能神经元对 Mn 的神经毒性，此外，Mn 还会导致 PK2-GDNF 信号传导受损。 影响 OB 功能和纹状体神经元存活所需的神经发生 充分确定其作用。 锰诱导的神经毒性损伤期间 BG 和嗅觉区的 PK2-GDNF 轴，我们将系统地 追求以下具体目标：（i）绘制 BG、OB、室下区 (SVZ) 的差异 PK2 表达图， 和嘴部迁移流 (RMS) 区域，并在功能上与神经发生、大脑区域特异性相关 (ii) 确定慢性锰神经毒性小鼠模型的神经元脆弱性和神经行为缺陷； PK2是否调节GDNF水平并表征PK2信号调节的分子机制 Mn 神经毒性细胞和动物模型中的 GDNF；以及 (iii) 评估转化神经保护功效 新型 PK2 受体激动剂和 AAV-PK2/GDNF 基因治疗在锰神经毒性动物模型中的研究 我们预测我们提出的研究将为金属诱导的 BG 和嗅觉提供新的机制见解 功能障碍及其在环境相关帕金森病发病机制中的作用，并将提供一种新的方法 治疗策略。