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.

抽象的 这项拨款申请的广泛、长期目标是了解涉及的机制 sigma 1 受体 (S1R) 激动剂的神经保护作用可治疗阿尔茨海默病 (AD)。最近的临床和 临床前数据表明，S1R 的激活可能会促进神经元弹性并导致突触保护 以及 AD 背景下的神经保护作用。 S1R 突变与运动退化有关 神经元和 SIGMA1R 基因的多态性与患迟发性 AD 的风险有关。 这些联系促使正在进行和计划中的 S1R 激动剂治疗 AD 的 2 期和 3 期临床试验 患者。尽管 S1R 对于神经元生理学和作为药物靶标很重要，但它的生物学功能是 对S1R激动剂的了解甚少，其作用机制在临床前和临床研究中尚不清楚 已确立的。该拨款提案的主要目的是评估突触保护作用的假设 S1R 激动剂在 AD 中的神经保护作用部分是通过其重塑 线粒体相关膜 (MAM) 和其他富含胆固醇的内质网 (ER) 微域。该假设基于我们最近发现的 S1R 关联的生物学重要性 与胆固醇及其在形成 MAM 和 ER 微结构域中的作用。为了检验这个假设，我们特别 将 (1) 研究 S1R 序列中胆固醇结合位点对于 AD 体内突触救援的重要性 老鼠； (2)分析AD中S1R激活对MAMs脂质组成变化的影响； (3) 确定 星形胶质细胞增强 ApoE 释放对 S1R 激动剂神经保护作用的作用； (4) 建立一个 S1R 激活引起的神经元钙信号传导变化的重要性。获得的结果 拟议的研究将提供有关模型中 S1R 激动剂作用机制的重要信息 AD 的研究，有助于解释正在进行的 S1R 激动剂 AD 临床试验，并有可能导致开发 下一代 AD 治疗 S1R 靶向治疗药物的研究。