Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性

基本信息

批准号：
10015358
负责人：
Rong Grace Zhai
金额：
$ 32.16万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015358
关键词：
Affect Aldehydes Antioxidants Autophagocytosis Biogenesis Biology Blood Bone Marrow Brain Brain Injuries Catabolism Cells Data Disease Disease Progression Drosophila genus Enzymes Family Fibroblasts Functional disorder Gene Library Genes Genetic Genetic Diseases Glutathione S-Transferase Goals Human Hydrogen Peroxide Hypoxia Image Intervention Ischemic Brain Injury Life Lysosomes Membrane Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mutation Nervous system structure Neurologic Symptoms Neurons Online Mendelian Inheritance In Man Outcome Oxidation-Reduction Oxidative Stress Pathologic Pathology Pathway interactions Patients Pharmacology Phenotype Polyamine Catabolism Polyamines Proteins Putrescine Reactive Oxygen Species Role Skin Snyder-Robinson syndrome Spermidine Spermine Spermine Synthase Stroke Stromal Cells Survival Rate Synapses Syndrome Testing Tissues Toxic effect Traumatic Brain Injury Work X-linked intellectual disability aldehyde dehydrogenases biobank bone causal variant cell type cellular pathology in vivo inhibitor/antagonist insight lymphoblast metabolic profile mutant nervous system disorder neuropathology neurotoxicity oxidation polycation response trafficking transcriptomics

项目摘要

Neurotoxicity of Spermine Synthase-Deficiency and Polyamine Imbalance PROJECT SUMMARY Polyamines, namely spermidine, spermine, and their precursor putrescine are tightly regulated polycations essential for life. Dysregulation of polyamine metabolism has been observed to accompany several neurological disease conditions include hypoxic and ischemic brain damage. However, the pathological consequence of polyamine imbalance in the nervous system remains unclear. The pivotal role of polyamine metabolism in the nervous system recently emerged with the mapping of causal mutation of Snyder-Robinson Intellectual Disability Syndrome (SRS, OMIM 309583) to spermine synthase (SMS), an enzyme that catalyzes the conversion of spermidine to spermine. SRS is the first confirmed genetic disorder associated with the polyamine metabolic pathway. Neurological manifestations in SRS indicate the long-term pathological consequence of polyamine imbalance, and provide a unique opportunity to uncover nervous system-specific function of SMS and polyamine metabolism. We have established a Drosophila model for SRS and found that human and Drosophila SMS proteins are functionally conserved, and loss of SMS in Drosophila recapitulated several key features of SRS pathology, including polyamine imbalance, reduced survival rate, and synaptic dysfunction. We discovered that SMS deficiency leads to excessive spermidine catabolism, and consequent lysosomal dysfunction and oxidative stress in vivo. We hypothesize that spermidine/spermine imbalance due to SMS deficiency causes altered polyamine catabolism, and that neutralizing the detrimental metabolites from polyamine catabolism will ameliorate phenotypes and disease progression in SRS. In this application, we will characterize the neuronal function of SMS in vivo, analyze the neurotoxicity resulted from polyamine imbalance, study cellular phenotypes in SRS patient blood lymphoblast, skin fibroblast and bone BMSC cells, and further discover genetic suppressors and potential pharmacological interventions for SRS. The proposed work will provide significant and important insights into the function of polyamines and SMS, and delineate the neuronal mechanisms underlying the neuropathology of spermine synthase-deficiency, and have long-lasting and sustained impact on polyamine-associated neurological disorders.

精胺合酶缺乏和多胺失衡的神经毒性项目概要多胺，即亚精胺、精胺及其前体腐胺受到严格监管生命必需的聚阳离子。据观察，多胺代谢失调伴随着一些神经系统疾病包括缺氧和缺血性脑损伤。然而，病理性神经系统多胺失衡的后果仍不清楚。多胺的关键作用最近随着斯奈德-罗宾逊因果突变的绘制，神经系统的新陈代谢出现了智力障碍综合症（SRS，OMIM 309583）精胺合成酶（SMS），一种催化酶亚精胺转化为精胺。 SRS 是第一个被证实与 SRS 相关的遗传性疾病多胺代谢途径。 SRS 中的神经学表现表明长期病理学多胺失衡的后果，并提供了发现神经系统特异性的独特机会 SMS 和多胺代谢的功能。我们建立了果蝇SRS模型并发现人类和果蝇 SMS 蛋白在功能上是保守的，果蝇中 SMS 的丢失得到了重现 SRS 病理学的几个关键特征，包括多胺失衡、存活率降低和突触功能障碍。我们发现 SMS 缺陷会导致亚精胺分解代谢过度，从而导致溶酶体功能障碍和体内氧化应激。我们假设亚精胺/精胺不平衡是由于 SMS 缺乏会导致多胺分解代谢改变，并中和来自多胺分解代谢将改善 SRS 的表型和疾病进展。在这个应用程序中，我们将表征SMS体内神经元功能，分析多胺引起的神经毒性失衡，研究 SRS 患者血液淋巴母细胞、皮肤成纤维细胞和骨 BMSC 细胞的细胞表型，并进一步发现 SRS 的基因抑制因子和潜在的药理学干预措施。拟议的这项工作将为多胺和 SMS 的功能提供重要的见解，并描绘出精胺合酶缺乏症神经病理学的神经机制，并具有长期持续的作用以及对多胺相关神经系统疾病的持续影响。