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.

项目摘要 蓝斑（LC）是一个脆弱的大脑区域，与神经退行性疾病有关， AD/ADRD。LC已被证明是AD/ADRD中最早退化的脑区之一，并且LC 变性与AD/ADRD中的疾病发病机制相关。在我们的工作从家长奖 （R 01 NS 121618），我们通过以下方式显示Gpt 2-null小鼠证明了已知最早的LC神经元损失： 出生后第18天，在任何遗传小鼠模型尚未研究。先前的研究也表明，LC 在AD/ADRD的几种小鼠模型中发生变性，尽管这种变性发生在生命后期 例如在6个月大时。LC神经元易损性的潜在机制 AD/ADRD未知;因此，通过研究Gpt 2- AD/ADRD中LC脆弱性的介导机制。本补编的首要目标 申请，这是强烈符合家长奖，是：1）开始定义Gpt 2介导的 LC脆弱性的线粒体机制;和2）确定这些Gpt 2介导的 机制是AD/ADRD遗传模型中LC脆弱性的基础Gpt 2介导机制的阐明 在LC神经元死亡和AD/ADRD中，将作为AD/ADRD治疗的新途径的基础， 包括在母申请中测试的潜在代谢物补充剂。之研究 补充申请还将允许成立一个合作小组，以调查LC的机制 AD/ADRD的脆弱性和收集后续AD/ADRD赠款申请的初步数据。的 在Gpt 2基因敲除小鼠中发现的突出和早期LC神经变性代表了一个重要的 有机会推进与AD/ADRD相关的LC研究。总之，这条新的AD/ADRD研究路线 将对AD/ADRD领域产生持续影响，因为研究涉及LC的临床相关主题 AD/ADRD中的神经变性，并有望建立新的代谢治疗方法。