Mechanisms of disease and treatment in novel metabolic developmental brain disorders

新型代谢性发育性脑疾病的疾病机制和治疗

• 批准号: 10712302
• 负责人: Eric M Morrow
• 金额: $ 31.42万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712302
• 关键词: Acceleration; Address; Administrative Supplement; Age Months; Alleles; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Model; Animals; Applications Grants; Area; Award; Brain; Brain Diseases; Brain region; Citric Acid Cycle; Collection; Communities; Data; Defect; Development; Disease; Electrophysiology (science); Foundations; Genetic; Genetic Models; Goals; Health; Heterozygote; Intervention; Investigation; Knockout Mice; Life; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parents; Partner in relationship; Pathogenesis; Pathogenicity; Pathology; Patients; Preventive treatment; Process; Property; Protein Biosynthesis; Public Health; Research; Slice; Testing; Wakefulness; Work; clinically relevant; design; experimental study; follow-up; locus ceruleus structure; metabolomics; mouse model; mutant; nervous system disorder; neurogenetics; neuron loss; novel; postnatal; preclinical study

PROJECT SUMMARY The locus coeruleus (LC) is a vulnerable brain area implicated in neurodegenerative diseases such as AD/ADRD. LC has been documented as among the earliest brain regions to degenerate in AD/ADRD, and LC degeneration is correlated with disease pathogenesis in AD/ADRD. In our work from the Parent Award (R01NS121618), we show that the Gpt2-null mouse demonstrates the earliest known loss of LC neurons, by postnatal day 18, in any genetic mouse model yet studied. Prior studies have also demonstrated that LC degeneration occurs in several mouse models of AD/ADRD, although this degeneration occurs later in the life of the animal, such as at 6 months of age. The underlying mechanisms of LC neuronal vulnerability in AD/ADRD are unknown; therefore, there is a critical opportunity for progress through the investigation of Gpt2- mediated mechanisms in LC vulnerability in AD/ADRD. The overriding objectives of this Supplement Application, which are strongly in line with the Parent Award, are: 1) to begin to define Gpt2-mediated mitochondrial mechanisms of LC vulnerability; and 2) to determine the extent to which these Gpt2-mediated mechanisms underlie LC vulnerability in AD/ADRD genetic models. Elucidation of Gpt2-mediated mechanisms in LC neuron death, and in AD/ADRD, will serve as a foundation for novel paths to treatment in AD/ADRD, including potentially metabolite supplements being tested in the Parent Application. The research in the Supplement Application will also permit the formation of a collaborative team to investigate mechanisms of LC vulnerability in AD/ADRD and the collection of preliminary data for follow-up AD/ADRD grant applications. The finding of prominent and early LC neurodegeneration in the Gpt2-null mouse represents an important opportunity to advance LC research relevant to AD/ADRD. In summary, this new line of AD/ADRD research will have a sustained impact on the AD/ADRD field as the research addresses the clinically relevant topic of LC neurodegeneration in AD/ADRD and promises to build a path to new metabolic treatments.

项目概要 蓝斑（LC）是一个脆弱的大脑区域，与神经退行性疾病有关，例如 AD/ADRD。 LC 已被记录为 AD/ADRD 中最早退化的大脑区域之一，并且 LC 退化与 AD/ADRD 的疾病发病机制相关。在我们获得家长奖的作品中 (R01NS121618)，我们发现 Gpt2 缺失小鼠表现出已知最早的 LC 神经元损失，通过 出生后第 18 天，在任何尚未研究的遗传小鼠模型中。先前的研究还表明，LC 变性发生在几种 AD/ADRD 小鼠模型中，尽管这种变性发生在生命后期 动物的，例如6个月大时。 LC神经元脆弱性的潜在机制 AD/ADRD 未知；因此，通过 Gpt2 的研究取得进展是一个关键的机会—— AD/ADRD 中 LC 脆弱性的介导机制。本补充文件的首要目标 与家长奖强烈一致的申请是：1）开始定义 Gpt2 介导的 LC 脆弱性的线粒体机制； 2) 确定这些 Gpt2 介导的程度 AD/ADRD 遗传模型中 LC 脆弱性的机制。 Gpt2介导机制的阐明 LC 神经元死亡和 AD/ADRD 中的研究将作为 AD/ADRD 治疗新途径的基础， 包括在母申请中测试的潜在代谢补充剂。该研究在 补充申请还将允许组建一个协作团队来研究 LC 的机制 AD/ADRD 中的漏洞以及为后续 AD/ADRD 拨款申请收集初步数据。这 在 Gpt2 缺失小鼠中发现显着的早期 LC 神经变性代表了重要的 有机会推进与 AD/ADRD 相关的 LC 研究。总之，AD/ADRD 研究的这一新路线 由于该研究涉及 LC 的临床相关主题，将对 AD/ADRD 领域产生持续影响 AD/ADRD 中的神经退行性疾病有望为新的代谢治疗开辟一条道路。