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Mechanisms of neuronal network dysfunction in juvenile neuronal ceroid lipofuscinosis

幼年神经元蜡质脂褐质沉积症神经元网络功能障碍的机制

基本信息

批准号：
10004182
负责人：
Rebecca Clare Ahrens-Nicklas
金额：
$ 18.8万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004182
关键词：
3-Dimensional Address Adolescent Affect Afferent Pathways Age Automobile Driving Autopsy Award Basic Science Biochemical Biochemistry Blindness Brain CLN3 protein Cells Cessation of life Child Childhood Clinical Confocal Microscopy Data Defect Dementia Development Disease Disorder of neurometabolic regulation Doctor of Philosophy Electroencephalogram Electrophysiology (science)Excitatory Synapse Functional disorder Funding Future Gene therapy trial Genes Goals Hippocampus (Brain)Human Image Imaging Techniques Immunohistochemistry Incidence Individual Investigation Lead Learning Link Longevity Lysosomal Storage Diseases Measurement Measures Mediating Mentors Metabolic Metabolic Diseases Modeling Morphology Mus Mutation Nerve Degeneration Nervous System Physiology Neuraxis Neurocognitive Neurologic Neurologic Symptoms Neuronal Ceroid-Lipofuscinosis Neurons Neurosciences Outcome Paper Pathology Patients Perforant Pathway Phenotype Physicians Physiology Population Property Publications Scientist Secondary to Seizures Slice Spielmeyer-Vogt Disease Structure Symptoms Synapses Testing Therapeutic TimeLine Training Translating Variant Work base career dentate gyrus drug discovery enzyme replacement therapy experience granule cell imaging study improved improved functioning insight mouse model network dysfunction neural circuit neurobiotin neuronal circuitry neuropathology new therapeutic target novel novel strategies novel therapeutics patch clamp postnatal protein expression reconstruction response restoration skills symptomatic improvement synaptic function therapy development translational scientist voltage sensitive dye

项目摘要

PROJECT SUMMARY Most metabolic diseases, including two-thirds of lysosomal storage disorders (LSD) affect the brain. For many, including Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), it is not known how the biochemical defect induces central nervous system dysfunction. Studies have focused on cellular-level pathology, with few investigations of how metabolic defects disrupt functional neuronal circuits. Ultimately, disruption of brain networks leads to the symptoms, such as seizures and neurocognitive regression, that are devastating to patients. JNCL results from biallelic mutations in CLN3. How loss of CLN3 protein disrupts neurologic function is unclear. In preliminary work, I have demonstrated that JNCL mice, like human patients, have abnormal electroencephalograms, suggesting mice are a suitable model for circuit-level studies. On autopsy, JNCL brains show neurodegeneration and lysosomal storage accumulation; the hippocampus is especially vulnerable. In my preliminary voltage-sensitive dye imaging (VSDI) studies of the JNCL mouse hippocampus, I have found progressive changes in excitability. Also, recent studies of late-stage JNCL show synaptic dysfunction in the mouse hippocampus. However, in studies of late-stage disease it is impossible to parse which changes are due to the primary loss of CLN3 protein or secondary to widespread neuropathology. Gene and/or enzyme replacement therapy is being developed for many LSDs. While this is exciting, moving to gene-based treatment before we know if replacement will fix the patients is problematic. Where and when to rescue protein expression is unclear. A major unanswered question is if correction of the biochemical defect underlying a metabolic disease will rescue the function of neuronal networks and improve symptoms. My central hypothesis is that in JNCL, hippocampal circuit pathology arises from synaptic dysfunction induced by loss of CLN3 protein. Because of the development of abnormal network dynamics, a vulnerable window may exist beyond which correction of single cell biochemistry will not correct functional defects. I will evaluate this by: 1) defining circuit level pathology using VSDI in two JNCL models; 2) exploring the synaptic and cellular changes driving network changes, and 3) assessing if rescue of CLN3 expression at different stages of disease can rescue circuit and synaptic dynamics. This work has important implications for future studies of the basic science of the CLN3 protein and novel therapies for JNCL. As an MD/PhD, I am passionate about translating basic science discoveries into new therapies for my patients with neurometabolic disorders. My mentors Dr. Eric Marsh, a physician-scientist neurogeneticist and electrophysiologist, and Dr. Beverly Davidson, a lysosomal storage disease expert, have devoted their careers to this goal. Under their guidance, I will use this 5-year experience to learn to apply my electrophysiology skills to studies of the brain and to prepare for a career as an independent R01-funded translational researcher.

项目概要大多数代谢疾病，包括三分之二的溶酶体贮积症 (LSD) 都会影响大脑。对于许多人来说，包括幼年神经元蜡质脂褐质沉着症（JNCL），目前尚不清楚生化缺陷如何诱发中枢神经系统功能障碍。研究主要集中在细胞水平的病理学上，很少有调查代谢缺陷如何破坏功能性神经元回路。最终，大脑网络的破坏导致癫痫发作和神经认知衰退等症状对患者来说是毁灭性的。 JNCL 是 CLN3 双等位基因突变的结果。 CLN3 蛋白的缺失如何破坏神经功能不清楚。在前期工作中，我已经证明 JNCL 小鼠与人类患者一样，具有异常脑电图，表明小鼠是电路级研究的合适模型。尸检时，JNCL 大脑出现神经变性和溶酶体储存积累；海马体尤其易受伤害的。在我对 JNCL 小鼠海马体的初步电压敏感染料成像 (VSDI) 研究中，我发现兴奋性逐渐变化。此外，最近对晚期 JNCL 的研究表明突触小鼠海马体功能障碍。然而，在晚期疾病的研究中，不可能解析这些变化是由于 CLN3 蛋白的原发性丢失或继发于广泛的神经病理学所致。正在为许多 LSD 开发基因和/或酶替代疗法。虽然这令人兴奋，但转向在我们知道替代疗法是否能治愈患者之前进行基于基因的治疗是有问题的。何时何地救援蛋白的表达尚不清楚。一个尚未解答的主要问题是是否可以纠正生化缺陷潜在的代谢疾病将挽救神经元网络的功能并改善症状。我的中心假设是，在 JNCL 中，海马回路病理是由突触功能障碍引起的 CLN3 蛋白的丢失。由于网络动态的异常发展，易受攻击的窗口可能存在超出该范围的单细胞生物化学校正将无法纠正功能缺陷。我会评价这是通过以下方式实现的：1) 在两个 JNCL 模型中使用 VSDI 定义电路级病理学； 2）探索突触和细胞变化驱动网络变化，3) 评估是否在不同阶段挽救 CLN3 表达疾病可以挽救神经回路和突触动力学。这项工作对未来的研究具有重要意义 CLN3 蛋白的基础科学和 JNCL 的新疗法。作为一名医学博士/博士，我热衷于将基础科学发现转化为患者的新疗法患有神经代谢紊乱。我的导师埃里克·马什 (Eric Marsh) 博士是一位医师科学家神经遗传学家电生理学家和溶酶体贮积病专家 Beverly Davidson 博士将他们的职业生涯奉献给了为了这个目标。在他们的指导下，我将利用这5年的经验来学习应用我的电生理学技能进行大脑研究，并为成为 R01 资助的独立转化研究员的职业生涯做好准备。