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: 10378088
• 负责人: Jun Hua
• 金额: $ 63.56万
• 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/10378088
• 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; Genetic; Goals; Histologic; Histology; Human; Image; Imaging Techniques; 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; Physiologic pulse; Pilot Projects; Play; Predisposition; Process; Psychophysics; Role; Signal Transduction; Speed; Structural defect; Structure; System; Techniques; Testing; Time; Treatment Efficacy; Vascular blood supply; Venous; Waste Products; alpha Toxin; arteriole; base; 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 approach; imaging biomarker; imaging modality; imaging study; inhibitor; lymphatic malformations; lymphatic vessel; motor deficit; mouse model; mutant; novel; quantitative imaging; research clinical testing; spatiotemporal; 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.

摘要：帕金森氏病（PD）是最常见的神经退行性疾病 没有治疗疗法。 关于大脑神经病理异常的主观和无信息。 早期诊断和治疗评估对疾病的预后至关重要。 大脑，淋巴系统和结构异常，导致多巴胺能丧失 神经元和运动障碍。 组织灌注以递送营养和氧气，以提供神经元和其他细胞的代谢需求， 而淋巴管在清除脑组织中的废物中起着至关重要的作用。 小血管的脉动波是淋巴管中流体的主要驱动力，主题 血管周间空间。 发病机理。我们最近开发了几种新的MRI（磁共振成像） 用于测量人类和动物的脑脑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的假设 可以通过新颖的MRI技术通过PD的发展和进步来衡量，而质量 可以作为致病过程和信任评估的潜在指标。 （Leucine富含重复激酶2）引起遗传PD并促进零星PD。 LRRK2 Mousel显示出强大的PD表型，并为MRI提供了出色的模型 评估MRI措施可以使用LRRK2小鼠模型中的侵入性技术验证 组织学方法。 这些小鼠的时期。 因此，我们建议使用新的MRI方法来研究脑病理学的变化 使用有或没有MPTP的LRK2小鼠模型（a​​） 通过合并 行为测试和大脑组织化学研究。 LRRK2小鼠模型中的容器2。 LRRK2小鼠模型中的大脑中的淋巴管。 脑微血管和淋巴管之间的相互作用，并评估脑脑和 淋巴测量可用于评估L-DOPA，LRK2激酶和GTP结合的治疗功效 抑制剂。 发病机理，可能有助于开发用于诊断和PD国际的生物标志物。