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.

精子缺乏和多胺失衡的神经毒性项目摘要多胺，即精子，精子及其前体perrescine受到严格调节多阳性对生命必不可少。观察到多胺代谢的失调伴随着几个神经系统疾病的疾病包括缺氧和缺血性脑损伤。但是，病理神经系统中多胺失衡的后果尚不清楚。多胺的关键作用神经系统中的代谢最近随着斯奈德 - 罗宾逊因果突变的映射而出现智力残疾综合征（SRS，OMIM 309583）至精子合酶（SMS），这是一种催化的酶精子转化为精子。 SRS是与多胺代谢途径。 SRS中的神经表现表明长期病理多胺失衡的结果，并为发现特定于神经系统的独特机会 SMS和多胺代谢的功能。我们已经建立了SRS的果蝇模型，发现人和果蝇SMS蛋白在功能上是保守的，果蝇中SMS的丢失概括 SRS病理学的几个关键特征，包括多胺不平衡，生存率降低和突触功能障碍。我们发现SMS缺乏会导致精子过多的分解代谢，因此体内溶酶体功能障碍和氧化应激。我们假设精子/精子不平衡应得 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。在此应用程序中，我们将表征SMS在体内的神经元功能，分析由多胺产生的神经毒性 SRS患者血液淋巴细胞，皮肤成纤维细胞和骨BMSC细胞中的细胞表型不平衡，研究细胞表型，并进一步发现了SRS的遗传抑制和潜在的药理干预措施。提议工作将为多胺和SMS的功能提供重要而重要的见解，并描述精子合酶缺陷的神经病理学基础的神经元机制，具有长期的并对多胺相关的神经系统疾病产生持续影响。