Sigma 1 receptor as therapeutic target for Alzheimers disease treatment

Sigma 1 受体作为阿尔茨海默病治疗靶点

• 批准号: 10901028
• 负责人: Ilya B Bezprozvanny
• 金额: $ 70万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2024-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901028
• 关键词: Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Applications Grants; Astrocytes; Binding; Binding Sites; Biological; Biological Process; Brain; Calcium; Calcium Signaling; Cell Line; Cells; Cholesterol; Clinical; Clinical Data; Clinical Research; Clinical Trials; Data; Dementia; Dependovirus; Development; Drug Targeting; Elderly; Endoplasmic Reticulum; Family; Freezing; Genes; Genetic Polymorphism; Glial Fibrillary Acidic Protein; Health; Hippocampus; Human; Knockout Mice; Late Onset Alzheimer Disease; Lentivirus; Link; Lipids; Liver; Long-Term Potentiation; LoxP-flanked allele; Measurement; Mediating; Membrane; Mitochondria; Morphology; Mus; Mutation; Neurons; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Physiology; Protein Isoforms; Public Health; Receptor Activation; Risk; Role; Sampling; Shotguns; Site; Slice; Stress; Synapses; Testing; Toxic effect; Vertebral column; Virus; conditional knockout; experimental study; in vivo; inhibitor; knock-down; lipidomics; motor neuron degeneration; mutant; neuroprotection; next generation; pharmacologic; pre-clinical; preclinical study; promote resilience; public health relevance; resilience; sigma-1 receptor; targeted treatment; therapeutic target; therapy development

ABSTRACT The broad, long-term objective of this grant application is to understand the mechanisms involved in neuroprotective action of sigma 1 receptor (S1R) agonists Alzheimer’s disease (AD). Recent clinical and preclinical data suggest that activation of S1R may promote neuronal resilience and result in synaptoprotective and neuroprotective effects within an AD context. Mutations in S1R are linked with degeneration of motor neurons and polymorphisms in SIGMA1R gene have been linked with the risk of developing late onset AD. These links have prompted on-going and planned phase 2 and phase 3 clinical trials of S1R agonists in AD patients. Despite its importance for neuronal physiology and as a drug target, the biological function of S1R is poorly understood and mechanism of action of S1R agonists in preclinical and clinical studies is not well established. The main aim of this grant proposal is to evaluate the hypothesis that synaptoprotective and neuroprotective effects of S1R agonists in AD are mediated in part by their remodeling of mitochondria-associated membranes (MAMs) and other endoplasmic reticulum (ER) cholesterol-rich microdomains. This hypothesis is based on our recent discovery of biological importance of S1R association with cholesterol and its role in forming MAMs and ER microdomains. To test this hypothesis, specifically we will (1) investigate an importance of cholesterol-binding site in S1R sequence for in vivo synaptic rescue in AD mice; (2) analyze effects of S1R activation on changes of lipid composition of MAMs in AD; (3) determine a role of enhanced ApoE release from astrocytes for neuroprotective effects of S1R agonists; (4) establish an importance of neuronal calcium signaling changes resulting from S1R activation. Results obtained in the proposed studies will provide essential information regarding mechanism of action of S1R agonists in models of AD, facilitate interpretation of on-going AD clinical trials of S1R agonists, and potentially lead to development of the next generation of S1R-targeting therapeutic agents for AD treatment.

摘要 这项资助申请的广泛的长期目标是了解 σ 1受体（S1 R）激动剂阿尔茨海默病（AD）的神经保护作用。最近的临床和 临床前数据表明，S1 R的激活可能促进神经元的恢复，并导致突触保护作用。 和神经保护作用。S1 R突变与运动神经退行性变有关 神经元损伤和SIGMA 1 R基因多态性与晚发性AD的发病风险有关。 这些联系促使正在进行和计划进行的S1 R激动剂治疗AD的2期和3期临床试验 患者尽管S1 R对于神经元生理学和作为药物靶点的重要性，但其生物学功能仍有待进一步研究。 临床前和临床研究中对S1 R激动剂的作用机制了解不多， 确立了习这项拨款申请的主要目的是评估突触保护性神经元的假说， S1 R激动剂在AD中的神经保护作用部分是通过它们的重构介导的。 内质网相关膜（MAMs）和其他富含胆固醇的内质网（ER） 微域这一假设是基于我们最近发现的S1 R相关的生物学重要性 胆固醇及其在形成MAMs和ER微区中的作用。为了验证这个假设，我们 将（1）研究S1 R序列中胆固醇结合位点对于AD中体内突触拯救的重要性 小鼠;（2）分析S1 R激活对AD中MAMs脂质组成变化的影响;（3）测定AD中MAMs的脂质组成。 星形胶质细胞ApoE释放增强对S1 R激动剂神经保护作用的作用;（4）建立一种新的神经保护机制， S1 R激活引起的神经元钙信号变化的重要性。中获得的结果 拟议的研究将提供有关模型中S1 R激动剂作用机制的重要信息 有助于解释正在进行的S1 R激动剂的AD临床试验，并可能导致开发 下一代S1 R靶向治疗药物的研究进展。