The effects of skull malformations and intracranial hypertension on the glymphatic and meningeal lymphatic systems in craniosynostosis

颅缝早闭时颅骨畸形和颅内高压对类淋巴系统和脑膜淋巴系统的影响

• 批准号: 10574732
• 负责人: Max Tischfield
• 金额: $ 30.23万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574732
• 关键词: Abeta clearance; Acute; Address; Adolescent; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid deposition; Animal Model; Animals; Apert syndrome; Attenuated; Biological Assay; Blood Vessels; Brain; Central Nervous System; Cerebrospinal Fluid; Cervical lymph node group; Chotzen Syndrome; Chronic; Circulation; Clinic; Cognitive deficits; Complex; Craniosynostosis; Data; Development; Drainage procedure; Dura Mater; Dysplasia; Etiology; Excision; Fluid Balance; Functional disorder; Genetic; Growth; Growth Factor; Health; Hippocampus; Human; Impaired cognition; Impairment; Injury; Intercellular Fluid; Intracranial Hypertension; Intracranial Pressure; Joint structure of suture of skull; Legal patent; Ligation; Light; Liquid substance; Long-Term Effects; Lymphatic; Lymphatic System; Mannitol; Measures; Meningeal lymphatic system; Meninges; Methods; Modeling; Molecular; Mus; Mutation; Neurocognitive Deficit; Neurologic Deficit; Nutrient; Obstruction; Pathway interactions; Receptor Signaling; Recombinants; Recycling; Risk; Rodent; Secondary to; Senile Plaques; Signal Transduction; Surgical sutures; System; Systems Biology; TWIST1 gene; Testing; Therapeutic; Tracer; Transgenic Mice; Traumatic Brain Injury; VEGFC gene; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Venous; Waste Products; Work; abeta oligomer; age related; aged; aquaporin 4; brain health; brain tissue; cerebrospinal fluid flow; cerebrovascular; clinically significant; craniofacial disorder; cranium; familial Alzheimer disease; functional disability; gain of function mutation; gene therapy; glymphatic dysfunction; glymphatic system; improved; innovation; lymphatic drainage; lymphatic vessel; macromolecule; malformation; mouse model; new therapeutic target; novel; novel marker; perivascular channels; pharmacologic; pressure; prevent; regenerative therapy; stem cells; synergism; tau aggregation; tau-1; uptake; venous sinus; wasting; water channel

Abstract: Our work has shown that humans with craniosynostosis, the second most prevalent craniofacial disorder, have skull and cerebrovascular malformations that cause intracranial hypertension (i.e. raised pressure). The effects of raised intracranial pressure on cerebrospinal fluid (CSF) circulation and fluid balance in the central nervous system are unknown in craniosynostosis, a notable gap in the field. Our new findings in craniosynostosis animal models suggest that skull dysplasia and raised pressure impair CSF flow, brain perivascular waste clearance pathways (the glymphatic system), and the development of meningeal lymphatic vessels. Infusing fluorescent tracers into CSF reveals significant changes to circulation pathways, and less influx into brain tissue and outflow to surrounding meningeal lymphatic networks. Meningeal lymphatics, which grow in dura attached to the skull, are hypoplastic and less complex. Interestingly, highly branched segments specialized for CSF uptake and waste removal, known as “hotspots”, are poorly developed and/or missing. These novel findings are significant because the brain's glymphatic system and supporting meningeal lymphatic vessels are necessary to prevent β-amyloid plaque buildup and cognitive impairment. Collectively, these data form a central hypothesis; craniosynostosis causes raised intracranial pressure and altered CSF hydrodynamics that impair the development and functions of both the glymphatic and meningeal lymphatic systems. This, in turn, affects the clearance of waste and β- amyloid from the brain. We test this hypothesis using our innovative systems biology approach that integrates skull development with intracranial pressure, CSF flow, and the brain's glymphatic and lymphatic systems. In Aim 1, we use two genetic mouse models for craniosynostosis to test if impaired glymphatic (i.e. CSF) influx and efflux impede the clearance of β-amyloid oligomers injected into the brain. Next, we test if the clearance of β- amyloid plaques is reduced by generating mouse models for craniosynostosis and amyloid deposition that express five mutations found in familial Alzheimer's disease. We also test a mechanistic basis for glymphatic dysfunction in craniosynostosis, by examining if the polarization of Aquaporin-4 water channels to glial endfeet is perturbed. These glial (i.e. glymphatic) water channels facilitate CSF flow through perivascular spaces in the brain, and therefore waste exchange between CSF and brain interstitial fluid. In Aim 2, we test whether meningeal lymphatic deficits affect waste drainage to the cervical lymph nodes. We also explore a molecular mechanism for meningeal lymphatic deficits by testing if VEGF-C expression and the activation of VEGFR3 receptor signaling is affected. Collectively, our novel system and approaches can dissect interlocking mechanisms through which normal skull development controls CSF flow, brain waste clearance pathways, and meningeal lymphatic drainage. This work has profound clinical significance as deficits in glymphatic waste exchange and meningeal lymphatics in craniosynostosis may imply increased risks for β-amyloid plaque buildup and neurocognitive impairment.

抽象的： 我们的工作表明，患有颅突的人，第二个普遍存在的颅面疾病，患有 颅骨和脑血管畸形引起颅内高血压（即压力升高）。效果 中枢神经系统中脑脊液（CSF）情况的颅内压升高 系统在颅突变中未知，这是该领域的显着差距。我们在颅突变动物中的新发现 模型表明头骨发育不良和升高的压力会损害CSF流量，脑周围废物清除 途径（糖基体系）和脑膜淋巴管的发展。注入荧光 进入CSF的示踪剂揭示了循环途径的显着变化，而对脑组织和出口的影响较小 到周围的脑膜淋巴网络。脑膜淋巴管，生长在颅骨上的硬脑膜， 是肿瘤性且不复杂的。有趣的是，专门用于CSF吸收和浪费的高度分支细分市场 删除被称为“热点”，发达和/或缺失。这些新颖的发现很重要，因为 对于预防β-淀粉样蛋白是必要的 斑块积累和认知障碍。总的来说，这些数据构成了中心假设。颅突式症 导致颅内压升并改变CSF流体动力学，从而损害了发展和功能 糖和脑膜淋巴系统。反过来，这会影响废物的清除和β- 大脑的淀粉样蛋白。我们使用我们的创新系统生物学方法来检验该假设 颅内压，CSF流以及大脑的糖性和淋巴系统的发育。在 AIM 1，我们使用两个遗传小鼠模型进行颅突式症来测试是否受损乙二醇（即CSF）的影响和 外排阻碍注入大脑的β-淀粉样蛋白低聚物的清除。接下来，我们测试β-的清除率是否 通过生成用于颅突的小鼠模型和淀粉样蛋白沉积的小鼠模型来减少淀粉样蛋白斑块 在家族性阿尔茨海默氏病中发现的五个突变。我们还测试了糖基的机械基础 颅突的功能障碍，通过检查Aquaporin-4水通道的极化与Glial Endfeet的极化 受到干扰。这些神经胶质（即甘氨酸）水道有助于CSF流经周围的周围空间 大脑，因此在CSF和大脑间质液之间交换。在AIM 2中，我们测试是否 脑膜淋巴缺陷会影响宫颈淋巴结的废物排水。我们还探索分子 通过测试VEGF-C表达和VEGFR3的激活，脑膜淋巴防御的机制 接收器信号受到影响。总的来说，我们的新型系统和方法可以剖析互锁 正常颅骨发育控制CSF流动，脑部浪费清除途径和 脑膜淋巴引流。这项工作具有高糖性废物中定义的深刻临床意义 颅突中毒中的交换和脑膜淋巴细胞计学可能意味着增加β-淀粉样菌斑积聚的风险 和神经认知障碍。