Precision Targeting of Heteromeric NMDA Receptors in Age-Related Memory Disorders

异聚 NMDA 受体在年龄相关记忆障碍中的精确靶向

• 批准号: 10624931
• 负责人: Joseph Aloysius McQuail
• 金额: $ 18.95万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624931
• 关键词: Age-Related Memory Disorders; Aging; Alzheimer' s Disease; Biochemical; Elderly; Glutamate Receptor; Hippocampus; Learning; Ligands; Longevity; Memory; Memory Loss; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Neurophysiology - biologic function; Population; Protein Isoforms; Severities; Symptoms; United States; age related; aging brain; innovation; novel therapeutics; prevent; targeted treatment; therapeutically effective; tool

The senior citizen population in the United States is growing, so new therapeutics to treat age-related memory loss are needed to protect personal independence and reduce the burden of Alzheimer’s disease (AD). Ionotropic glutamate receptors of the NMDA subtype (NMDARs) are necessary for normal learning and memory, but NMDAR-targeting therapeutics are minimally effective in lessening the severity of AD symptoms and are not approved to treat memory loss in non-pathological brain aging. NMDARs are biochemically diverse tetramers formed between GluN1 and GluN2 subunits. GluN2A and GluN2B isoforms are abundantly expressed in the hippocampus, but selective ligands that target GluN2A or GluN2B have produced conflicting accounts of NMDAR contribution to memory and neural functions over the lifespan. Unexplored are contributions of tri-heteromeric NMDARs that contain GluN1, GluN2A and GluN2B. This project will innovate the scientific study of NMDARs by developing new ligands that are selective for the GluN1/GluN2A/GluN2B tri-heteromeric NMDAR and investigate how naturally occurring and experimentally induced changes in GluN2 isoforms regulate formation of tri-heteromers in the aging brain. These studies will be significant because they will create new tools to target a broader range of naturally occurring heteromeric NMDARs and identify how interactions between GluN2 isoforms influence neural function in brain aging. Ultimately, these discoveries will open new avenues to develop NMDAR-targeting therapeutics that are effective in preventing or reversing memory loss that emerges in advanced aging.

美国的老年人口正在增长，因此治疗与年龄相关的新疗法 需要记忆丧失来保护个人独立性并减轻阿尔茨海默病的负担 (AD) NMDA 亚型离子型谷氨酸受体 (NMDAR) 对于正常学习是必需的。 和记忆力，但 NMDAR 靶向疗法在减轻 AD 严重程度方面效果甚微 NMDAR 没有被批准用于治疗非病理性脑老化引起的记忆丧失。 GluN1 和 GluN2 亚基之间形成生物化学多样化的四聚体。 在海马中大量表达，但靶向 GluN2A 或 GluN2B 的选择性配体具有 对于 NMDAR 在整个生命周期中对记忆和神经功能的贡献产生了相互矛盾的说法。 尚未探索的是包含 GluN1、GluN2A 和 GluN2B 的三异聚 NMDAR。 该项目将通过开发选择性的新配体来创新 NMDAR 的科学研究 GluN1/GluN2A/GluN2B 三异聚 NMDAR 并研究如何自然发生和实验 这些研究表明，GluN2 异构体的诱导变化可调节衰老大脑中三异质体的形成。 将会很重要，因为他们将创建新的工具来针对更广泛的自然发生的 异聚 NMDAR 并确定 GluN2 异构体之间的相互作用如何影响神经功能 最终，这些发现将为开发 NMDAR 靶向疗法开辟新途径。 可有效预防或逆转晚期衰老中出现的记忆丧失。