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Neuroinflammatory Biomarkers for Nigrostriatal Injury

黑质纹状体损伤的神经炎症生物标志物

基本信息

批准号：
10624405
负责人：
JOEL Synes PERLMUTTER
金额：
$ 63.22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624405
关键词：
Address Animals Anti-Inflammatory Agents Area Attenuated Biological Markers Brain Brain Stem Cell Nucleus Clinical Trials Corpus striatum structure Data Deposition Diffusion Magnetic Resonance Imaging Dopamine Drug Targeting Fiber Functional disorder Goals Histologic Human In Vitro Infusion procedures Injury Investigation Magnetic Resonance Magnetic Resonance Imaging Measures Medial Motor Motor Cortex Motor Manifestations Nerve Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Neurotransmitters Olfactory tubercle Osmosis Parkinson Disease Parkinsonian Disorders Pathogenesis Pathogenicity Pathology Pathway interactions Persons Placebos Positron-Emission Tomography Process Pump Reactive Oxygen Species Reporting Retrograde Degeneration Testing Training alpha synuclein attenuation brain tissue disability imaging biomarker implantation in vivo intraperitoneal kinematics motor symptom nerve damage neuroimaging marker neuroinflammation nigrostriatal degeneration nigrostriatal dopaminergic pathway nonhuman primate novel novel therapeutics prevent radiotracer response

项目摘要

ABSTRACT. Parkinson disease (PD) causes motor and nonmotor manifestations. Underlying pathology includes abnormal deposition of α-synuclein (α-syn) starting in caudal brainstem (as well as olfactory tubercle and medial temporal areas) and then spreads to more rostral brainstem and cortical areas. Initial motor manifestations likely reflect degeneration to the nigrostriatal dopaminergic pathway but cortical dysfunction leading to nonmotor and some motor manifestations may reflect direct α-syn involvement, neurotransmitter deficiencies due to loss of projecting brainstem nuclei or secondary dysfunction of cortical or subcortical networks. Currently, no treatment delays the relentless progression of PD. We have preliminary data (neuroinflammation, increased reactive oxygen species) after nigrostriatal injury in nonhuman primates (NHPs) that suggests that cortical dysfunction may occur from retrograde degeneration along cortico-striatal neurons. Here we will test whether an anti-inflammatory compound, synoxizyme (previously called carboxyfullerene or C3), will reduce the observed neuroinflammation, and prevent retrograde cortical injury as a potential mechanism which could contribute to disability in people with PD. We will confirm this finding and validate in vivo PET measures of neuroinflammation and reactive oxygen species. We also demonstrated that synoxizyme restores nigrostriatal dysfunction after unilateral internal carotid (ic) infusion of the selective neurotoxin MPTP. Synoxizyme may act through attenuation of neuroinflammation and reduce destructive reactive oxygen species. Another goal of this study is to determine whether our new PET radiotracers can act as targets of engagement for synoxizyme. These highly novel studies will determine whether nigrostriatal injury with MPTP in nonhuman primates leads to cortical dysfunction which could provide the basis for investigations into another mechanism of cortical dysfunction that occurs in people with PD. Furthermore, we will validate new PET measures of neuroinflammation and reactive oxygen species that could be key for such studies. We will determine whether diffusion tensor imaging MR measures of mean diffusivity identify cortical striatal tract dysfunction that could support the notion of retrograde degeneration after nigrostriatal injury. We also will determine whether systemically administered synoxizyme will attenuate the effects of MPTP and whether this corresponds with a reduction in MPTP-induced neuroinflammation and increased reactive oxygen species – which may be involved in the pathogenesis of human PD. Finally, we will be able to demonstrate whether the PET measures may provide quantification of targets of engagement for synoxizyme, which would be critical information for a subsequent clinical trial in humans of synoxizyme or any other treatment targeting these pathogenic mechanisms in PD or other neurodegenerative conditions.

摘要。帕金森病（PD）引起运动和非运动表现。基础病理学包括异常 α-synuclein（α-syn）的沉积始于尾侧脑干（以及嗅结节和内侧颞区），然后扩散到更多的喙脑干和皮质区。初始运动表现可能反映黑质纹状体多巴胺能通路的退化，但皮质功能障碍导致非运动和一些运动表现可能反映直接α-syn参与，神经递质缺乏由于投射脑干核团的丢失或皮质或皮质下网络的继发性功能障碍。目前，没有治疗可以延缓PD的无情进展。我们有初步的数据（神经炎症，非人灵长类动物（NHP）黑质纹状体损伤后活性氧增加，这表明，皮质功能障碍可由沿着皮质-纹状体神经元的逆行变性沿着而发生。在这里我们将测试一种抗炎化合物，synoxizyme（以前称为羧基富勒烯或C3），是否会减少观察到的神经炎症，并防止逆行性皮质损伤作为一个潜在的机制，会导致PD患者的残疾我们将证实这一发现，并验证体内PET措施，神经炎症和活性氧。我们还证明了突触合酶可以恢复黑质纹状体单侧颈内动脉（ic）灌注选择性神经毒素MPTP后功能障碍。Synoxizyme可能起作用通过减轻神经炎症和减少破坏性的活性氧。另一个目标是这项研究的目的是确定我们的新PET放射性示踪剂是否可以作为结合酶的靶点。这些高度新颖的研究将确定非人类灵长类动物中MPTP引起的黑质纹状体损伤是否会导致皮质功能障碍，这可以为研究皮质功能障碍的另一种机制提供基础。帕金森病患者的功能障碍此外，我们将验证新的PET措施，神经炎症和活性氧可能是这些研究的关键。我们将决定扩散张量成像MR测量平均扩散率可以识别皮质纹状体束功能障碍，支持黑质纹状体损伤后退行性变的概念。我们还将确定全身给药的synoxizyme将减弱MPTP的作用，以及这是否与减少MPTP诱导的神经炎症和增加活性氧-这可能是参与人类PD的发病机制。最后，我们将能够证明PET是否可以测量可以提供参与synoxizyme的目标的量化，这将是一个关键信息，随后在人类中进行Synoxizyme或任何其它靶向这些致病性 PD或其他神经退行性疾病的机制。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Determinants of gait dystonia severity in cerebral palsy.

脑瘫步态肌张力障碍严重程度的决定因素。

DOI：
10.1111/dmcn.15524
发表时间：
2023
期刊：
Developmental medicine and child neurology
影响因子：
3.8
作者：
Aravamuthan,BhoomaR;Pearson,ToniS;Ueda,Keisuke;Miao,Hanyang;Zerafati-Jahromi,Gazelle;Gilbert,Laura;Comella,Cynthia;Perlmutter,JoelS
通讯作者：
Perlmutter,JoelS

Synthesis and evaluation of highly selective quinazoline-2,4-dione ligands for sphingosine-1-phosphate receptor 2.

1-磷酸鞘氨醇受体 2 的高选择性喹唑啉-2,4-二酮配体的合成和评价。