Advanced MRI studies of cerebrovascular and lymphatic abnormalities in LRRK2 mouse models of Parkinson's disease

帕金森病 LRRK2 小鼠模型脑血管和淋巴异常的高级 MRI 研究

• 批准号: 10596558
• 负责人: Jun Hua
• 金额: $ 62.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596558
• 关键词: Animal Model; Animals; Arteries; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Pathology; Brain region; Cells; Cerebrovascular system; Cerebrum; Clinical; Contrast Media; Development; Diagnostic; Disease Progression; Evaluation; GTP Binding; Genes; Genetic; Goals; Histologic; Histology; Human; Image; Inflammatory; Intervention; LRRK2 gene; Levodopa; Lipopolysaccharides; Liquid substance; Longitudinal Studies; Lymphatic; Lymphatic System; Lymphatic clearance; Magnetic Resonance Imaging; Measures; Metabolic; Methodology; Methods; Modeling; Monitor; Movement Disorders; Mus; Mutation; Neurodegenerative Disorders; Neurons; Nutrient; Oxygen; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Perfusion; Phenotype; Phosphotransferases; Pilot Projects; Play; Predisposition; Process; Psychophysics; Role; Signal Transduction; Speed; Structural defect; Structure; System; Techniques; Testing; Time; Toxin; Treatment Efficacy; Vascular System; Vascular blood supply; Venous; Waste Products; arteriole; behavior measurement; behavior test; biomarker development; brain tissue; cerebral blood volume; cerebrovascular; curative treatments; disease prognosis; dopaminergic neuron; driving force; early detection biomarkers; human model; imaging biomarker; inhibitor; lymphatic malformations; lymphatic vessel; motor deficit; mouse LRRK2 protein; mouse model; mutant; neuron loss; neuropathology; novel; quantitative imaging; research clinical testing; spatiotemporal; sporadic Parkinson' s Disease; therapeutic evaluation

Abstract: Parkinson’s disease (PD) is the second-most common neurodegenerative disease. Currently there is no curative therapy. Clinical evaluation of PD has been limited to psychophysical assessment, which is subjective and uninformative with regard to brain neuropathological abnormalities. Developing biomarkers for early diagnostics and treatment evaluation is critical for disease prognosis. PD cases display brain cerebrovascular, lymphatic system and structural abnormalities which contribute to the loss of dopaminergic neurons and movement disorders. Small pial arteries and arterioles are the primary controls of local brain tissue perfusion for delivery of nutrients and oxygen to supply the metabolic needs of neurons, and other cells, while lymphatic vessels play a crucial role in the clearance of waste products from brain tissues. The arterial pulsation wave from small blood vessels is the primary driving force for the fluid in lymphatic vessels and the perivascular space. Imbalance in the interaction between the two systems may have implications for PD pathogenesis. We recently developed several new MRI (Magnetic resonance imaging) techniques that can be used to measure brain cerebrovascular and lymphatic system abnormalities in both humans and animal models. We propose to test the hypothesis that abnormalities in brain microvascular and lymphatic vessels can be measured by novel MRI techniques through PD development and progression, and that those abnormalities can serve as potential indicators for pathogenic processes and treatment evaluation. Mutations in LRRK2 (Leucine Rich Repeat Kinase 2) cause genetic PD and contribute to sporadic PD. We recently generated a LRRK2 mouse model that displayed a robust PD-like phenotype and provided an excellent model for MRI assessment. MRI measures can be validated with invasive techniques in LRRK2 mouse models using histological methods. The longitudinal study and therapeutic testing can be done in a relatively short time period in these mice. Our pilot study found that mutant G2019S-LRRK2 mice display cerebrovascular abnormalities. Thus, we propose to use new MRI methods to study brain pathophysiological changes in cerebrovascular and lymphatic vessels underlying PD using LRRK2 mouse models with or without MPTP (a toxin to speed disease progression) and lipopolysaccharide (a preinflammatory agent) challenge by combining behavioral testing and brain histochemical studies. Aim 1. We will assess abnormalities in brain small blood vessels in LRRK2 mouse models. Aim 2. We will assess abnormalities in the perivascular space and cerebral lymphatic vessels in the brain in LRRK2 mouse models. Aim 3. We will characterize the abnormalities in the interactions between brain microvascular and lymphatic vessels, and assess whether cerebrovascular and lymphatic measures can be used to evaluate treatment efficacy of L-DOPA, LRRK2 kinase and GTP binding inhibitors. These studies will advance our understanding of the neuropathological changes underlying PD pathogenesis, which may facilitate the development of biomarkers for diagnostics and PD intervention.

翻译后摘要：帕金森病（PD）是第二个最常见的神经退行性疾病。当前 不是治愈性疗法PD的临床评估仅限于心理物理评估， 关于脑神经病理学异常的主观的和无信息的。开发生物标志物， 早期诊断和治疗评估对疾病预后至关重要。PD病例显示大脑 脑血管，淋巴系统和结构异常，这有助于多巴胺能神经元的损失， 神经元和运动障碍。软脑膜小动脉和小动脉是局部脑的主要控制 用于输送营养物和氧气以供应神经元和其它细胞的代谢需要的组织灌注， 而淋巴管在清除脑组织中的废物方面起着至关重要的作用。动脉 来自小血管的脉动波是淋巴管中流体的主要驱动力， 血管周围间隙两个系统之间相互作用的不平衡可能对PD产生影响 发病机制我们最近开发了几种新的MRI（磁共振成像）技术， 用于测量人类和动物的脑血管和淋巴系统异常 模型我们建议检验脑微血管和淋巴管异常可以 通过新型MRI技术测量PD的发展和进展，并且这些异常 可以作为致病过程和治疗评价的潜在指标。LRRK 2突变 （富含亮氨酸重复激酶2）引起遗传性PD并促成散发性PD。我们最近生成了一个 LRRK 2小鼠模型显示出稳健的PD样表型，并为MRI提供了极好的模型 考核MRI测量可以使用侵入性技术在LRRK 2小鼠模型中验证， 组织学方法纵向研究和治疗试验可以在相对较短的时间内完成 在这些老鼠身上。我们的初步研究发现，突变G2019 S-LRRK 2小鼠表现出脑血管病变， 异常因此，我们建议使用新的MRI方法来研究脑病理生理变化， 使用具有或不具有MPTP的LRRK 2小鼠模型的脑血管和淋巴管作为PD的基础（a 毒素加速疾病进展）和脂多糖（一种前炎症因子）的挑战， 行为测试和脑组织化学研究。目标1.我们将评估大脑小血液的异常 LRRK 2小鼠模型中的血管。目标二。我们将评估血管周围空间和大脑的异常 LRRK 2小鼠模型中脑中的淋巴管。目标3.我们将描述 脑微血管和淋巴管之间的相互作用，并评估脑血管和 淋巴测量可用于评估L-DOPA、LRRK 2激酶和GTP结合的治疗功效 抑制剂的这些研究将进一步加深我们对帕金森病神经病理变化的认识 发病机制，这可能有助于诊断和PD干预的生物标志物的发展。