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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：
10457437
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/10457437
关键词：
3-Dimensional Address Adolescent Affect Afferent Pathways Age Automobile Driving Autopsy Award Basic Science Biochemical Biochemistry Blindness Brain CLN3 gene 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 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 juvenile neuronal ceroid lipofuscinosis 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.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders.

枫糖浆尿液疾病中的大脑分支链氨基酸：神经系统疾病的影响。

DOI：
10.3390/ijms21207490
发表时间：
2020-10-11
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Xu J;Jakher Y;Ahrens-Nicklas RC
通讯作者：
Ahrens-Nicklas RC

Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.

DOI：
10.1038/s41390-020-1101-5
发表时间：
2021-05
期刊：
Pediatric research
影响因子：
3.6
作者：
Burstein DS;Gaynor JW;Griffis H;Ritter A;Connor MJO;Rossano JW;Lin KY;Ahrens-Nicklas RC
通讯作者：
Ahrens-Nicklas RC

Heal thyself: The promise of autologous hematopoietic stem cell gene therapy in neurometabolic disorders.

治愈你自己：自体造血干细胞基因疗法在神经代谢疾病中的前景。

DOI：
10.1016/j.ymthe.2022.03.006
发表时间：
2022
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
Ahrens-Nicklas,RebeccaC
通讯作者：
Ahrens-Nicklas,RebeccaC

Fine-Tuning 3-Methylglutaconic Aciduria Cutoffs for a Patient with Infantile-Onset Barth Syndrome.

微调婴儿期巴斯综合征患者的 3-甲基戊二酸尿截止值。

DOI：
10.1093/clinchem/hvab167
发表时间：
2022
期刊：
Clinical chemistry
影响因子：
9.3
作者：
Alharbi,Hana;Hong,Xinying;Ritter,Alyssa;Ahrens-Nicklas,Rebecca;Master,StephenR;He,Miao
通讯作者：
He,Miao

Newborn Screening for Pompe Disease: Pennsylvania Experience.

DOI：
10.3390/ijns6040089
发表时间：
2020-11-13
期刊：
International journal of neonatal screening
影响因子：
3.5
作者：
Ficicioglu C;Ahrens-Nicklas RC;Barch J;Cuddapah SR;DiBoscio BS;DiPerna JC;Gordon PL;Henderson N;Menello C;Luongo N;Ortiz D;Xiao R
通讯作者：
Xiao R