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

基本信息

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
项目类别：
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&apos s disease model Alzheimer&apos 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

Acceleration Address Administrative Supplement Age Months Alleles Alzheimer&apos s disease model Alzheimer&apos 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

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项目摘要

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.

项目摘要基因座（LC）是涉及神经退行性疾病的脆弱脑区域广告/adrd。 LC已被记录为在AD/ADRD中退化的最早的大脑区域之一，LC 退化与AD/ADRD中的疾病发病机理相关。在父母奖的工作中（R01NS121618），我们表明，GPT2无效的小鼠证明了最早已知的LC神经元丧失，在尚未研究的任何遗传小鼠模型中，第18天后。先前的研究还表明LC 退化发生在AD/ADRD的几种小鼠模型中，尽管这种变性发生在生命的后期动物的含量，例如6个月大。 LC神经元脆弱性的基本机制广告/adrd是未知的；因此，通过调查GPT2-有一个至关重要的机会 LC/ADRD中LC脆弱性的介导机制。该补充的重要目标与父母奖一致的应用程序是：1）开始定义GPT2介导 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。阐明GPT2介导的机制在LC神经元死亡和AD/ADRD中，将成为AD/ADRD新颖治疗途径的基础包括在父申请中测试的潜在代谢物补充剂。在补充申请还将允许组建一个协作团队来调查LC的机制 AD/ADRD中的漏洞以及随访广告/ADRD赠款应用程序的初步数据的收集。这在GPT2-NULL小鼠中发现突出和早期LC神经退行性变性是重要的推进与AD/ADRD相关的LC研究的机会。总而言之，这一新的广告/ADRD研究系列由于研究涉及LC的临床相关主题，将对AD/ADRD领域产生持续的影响 AD/ADRD中的神经变性，并有望为新的代谢疗法建立一条途径。