A Novel Role for cMyc in Vascular Homeostasis

cMyc 在血管稳态中的新作用

• 批准号: 10092385
• 负责人: CLAUDIA OLIVEIRA RODRIGUES
• 金额: $ 3.16万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-12 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092385
• 关键词: Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Award; Behavioral; Blood Vessels; Brain; Dementia; Deterioration; Development; Early identification; Endothelium; Environmental Risk Factor; Goals; Homeostasis; Huntington Disease; Inflammation; Knockout Mice; Lead; Life Expectancy; Molecular; Multiple Sclerosis; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Parents; Parkinson Disease; Pathologic; Pathway interactions; Phenotype; Play; Prevention strategy; Public Health; Role; Stress; Testing; Work; c-myc Genes; cell type; neuroinflammation; neuroprotection; neurotoxic; neurovascular unit; novel; research study; tissue regeneration; tissue repair

Neurodegeneration is a hallmark of aging. Projection studies indicate that the increase in life expectancy will have a significant impact in the number of cases of different types of neurodegenerative conditions and become a serious public health concern. One of the main gaps in neurodegeneration is the identification of early molecular changes that lead to deterioration of the nervous systems in the context of aging and toxic environmental factors. Normal brain function depends on the efficient integration of different cell types that compose the neurovascular unit and work together to maintain homeostasis of the central nervous system. Inflammation plays an important role in tissue repair and regeneration. Conversely, deregulated inflammation can elicit different types of pathological conditions. Neuroinflammation and disruption of the neurovascular unit play a critical role on the development of several neurodegenerative conditions such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis and other types of dementia. The primary goal of this supplement proposal is to determine if endothelial c-Myc plays a role in brain homeostasis during aging and neurotoxic stress leading to neurodegeneration. Unpublished findings from our parent R01 suggest that endothelial c-Myc expression regulates neuroinflammation and neurodegeneration- associated pathways in the brain. This proposal will consist of additional studies associated with Aim 2 of the parent award, to determine if our animal model shows signs of behavioral and pathological changes commonly described in neurodegeneration. We propose to test the hypothesis that endothelial c-Myc is essential to maintain the neurovascular unit function and contribute to protection against neurodegenerative diseases. In Aim 1, we will characterize the brain phenotype of endothelial c-Myc knockout mice throughout aging in the context of neurodegeneration. In Aim 2, we will determine the relevance of endothelial c-Myc for neuroprotection. Our findings will have a significant impact by identifying a novel potential mechanism involved in neurodegeneration.

神经退行性变是衰老的标志。预测研究表明，预期寿命的增加将 对不同类型神经退行性疾病的病例数量产生重大影响，并成为 一个严重的公共卫生问题。神经退行性变的主要差距之一是早期神经退行性疾病的识别 在衰老和有毒的情况下导致神经系统恶化的分子变化 环境因素。正常的大脑功能取决于不同细胞类型的有效整合 组成神经血管单元并共同维持中枢神经系统的稳态。 炎症在组织修复和再生中起着重要作用。相反，炎症失调 可以引发不同类型的病理状况。神经炎症和神经血管单位的破坏 在阿尔茨海默病等多种神经退行性疾病的发展中发挥着关键作用， 帕金森病、亨廷顿病、肌萎缩侧索硬化症、多发性硬化症等 失智。 该补充提案的主要目标是确定内皮 c-Myc 是否在大脑中发挥作用 衰老过程中的稳态和导致神经变性的神经毒性应激。我们未发表的研究结果 亲本 R01 表明内皮 c-Myc 表达调节神经炎症和神经变性 - 大脑中的相关通路。该提案将包括与目标 2 相关的其他研究 家长奖，以确定我们的动物模型是否普遍表现出行为和病理变化的迹象 描述于神经变性。我们建议检验以下假设：内皮细胞 c-Myc 对于 维持神经血管单元功能并有助于预防神经退行性疾病。在 目标 1，我们将表征内皮 c-Myc 敲除小鼠在整个衰老过程中的大脑表型 神经退行性变的背景。在目标 2 中，我们将确定内皮 c-Myc 与神经保护的相关性。 我们的研究结果将通过确定一种新的潜在机制产生重大影响 神经变性。