Endogenous barcoding to determine complex dynamics of adult neurogenesis in aging and Alzheimer's disease

内源条形码确定衰老和阿尔茨海默病中成人神经发生的复杂动态

基本信息

批准号：
10846200
负责人：
GRIGORI N ENIKOLOPOV
金额：
$ 41.46万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10846200
关键词：
3-Dimensional Acquired Immunodeficiency Syndrome Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Animal Disease Models Animal Model Animals Anti-Retroviral Agents Bar Codes Behavior Behavioral Brain Brain Mapping Brain region Cells Clinical Cognitive Cognitive deficits Complex Conflict (Psychology)Data Set Disease Elderly Exposure to FOS gene Face Foundations Genetic Goals Grant HIV HIV Infections HIV-1 Hippocampus Impairment Individual Infection Injectable Label Life Expectancy Maps Memory Methods Molecular Mus Neuroanatomy Neurodegenerative Disorders Neurons Oral Parents Pathogenesis Persons Pharmaceutical Preparations Population Prevalence Process Proxy Regimen Risk Tenofovir Testing Therapeutic Intervention Three-Dimensional Imaging Time adult neurogenesis age related aging hippocampus aging population antiretroviral therapy brain circuitry clinically relevant cognitive function cognitive process cohort emtricitabine executive function experience experimental study improved in silico large scale production mortality mouse model nerve stem cell neural circuit neural network neurogenesis neuronal patterning novel novel strategies novel therapeutics pre-exposure prophylaxis social stem targeted treatment tool treatment response

项目摘要

1 ABSTRACT 2 3 The population of people living with HIV gradually ages, in part due to the efficiency of antiretroviral 4 therapy (ART) which has significantly improved the life expectancy of infected individuals. This aging population 5 inevitably faces an increased risk of developing neurodegenerative disorders including Alzheimer's disease (AD). 6 These concerns are 7 These deficits may be due solely to the HIV-1 infection; 8 however, this may also indicate that long-term ART itself contributes to the impairments. The latter possibility is 9 of particular concern given that a growing number of uninfected individuals employ use antiretrovirals (ARVs) as 10 pre-exposure prophylaxis (PrEP). The mechanisms underlying ART-induced changes and their impact on brain 11 circuitry that may be affected by prolonged treatment with ARVs are unclear; even less is known about the action 12 of ARVs in the aging and AD-afflicted brain. The mechanisms of ART-induced changes and the brain circuitry 13 that may be affected by prolonged treatment with ARVs are unclear; even less is known about the action of 14 ARVs in the aging and AD -afflicted brain. 15 We propose to apply our recently developed array of new tools for analyzing neurogenesis and for 16 constructing, comparing, and analyzing 3D whole-brain maps of neuronal activation in the mouse brain to reveal 17 the critical neural circuitry affected by representative ARVs. Our hypothesis is that 3D patterns of neuronal 18 activation in aging and AD model animals exposed to ARVs and involved in challenging behavioral tasks can 19 both reveal the crucial circuitry defining these effects and serve as unique signatures of the treatments’ 20 effects. Furthermore, our recent results demonstrate that treatment with ARVs can affect adult hippocampal 21 neurogenesis, thus indicating another potential vulnerability of the ARV-exposed aging and AD brain. This 22 proposal is directly related to the parent R01 grant which also focuses on the aging and AD brain. 23 In specific aim 1, we will determine the effect of prolonged treatment with representative ARVs on stem 24 cells and adult-born neurons in the hippocampus of aging and AD model mice. In specific aim 2, we will 25 determine the critical shared components of neural circuitry affected by prolonged exposure to select ARVs. We 26 will generate mesoscopic global maps of neuronal activation in aging and AD model mice presented with relevant 27 cognitive challenges after exposure to ARVs. We will then subject the mapping datasets to our stepwise selection 28 pipeline to identify the critical brain regions and neural circuits altered by the treatments. Our experiments will 29 reveal the effect of ARVs on hippocampal neurogenesis and will create a circuitry map space for the action of 30 ARVs upon which other circuitry maps that describe various responses to treatments in the context of aging and 31 AD can be projected and compared. 32 further compounded by the prevalence of cognitive deficits observed in a substantial proportion of HIV-1-infected individuals undergoing ART.

1 摘要 2 3 艾滋病毒感染者人口逐渐老龄化，部分原因是抗逆转录病毒药物的有效性 4 疗法（ART）显着提高了人口老龄化的感染者的预期寿命。 5 不可避免地面临着罹患包括阿尔茨海默病 (AD) 在内的神经退行性疾病的风险增加。 6 这些担忧是 7 这些缺陷可能仅仅是由于 HIV-1 感染所致； 8 然而，这也可能表明长期 ART 本身会造成损害。后一种可能性是。 9 特别值得关注的是，越来越多的未感染者使用抗逆转录病毒药物 (ARV) 作为治疗药物 10 暴露前预防 (PrEP) ART 引起的变化的机制及其对大脑的影响。 11 长期接受抗逆转录病毒药物治疗可能影响的电路尚不清楚；关于其作用更是知之甚少。 12 抗逆转录病毒药物在衰老和 AD 患者大脑中的作用 ART 引起的变化机制和大脑回路。 13 哪些因素可能受到长期抗逆转录病毒药物治疗的影响尚不清楚； 14 抗逆转录病毒药物治疗衰老和 AD 患者的大脑。 15 我们建议应用我们最近开发的一系列新工具来分析神经发生和 16 构建、比较和分析小鼠大脑神经激活的 3D 全脑图以揭示 17 受代表性抗逆转录病毒药物影响的关键神经回路我们的假设是神经的 3D 模式。 18 暴露于抗逆转录病毒药物并参与具有挑战性的行为任务的衰老和 AD 模型动物的激活可以 19 都揭示了定义这些效应的关键电路，并作为治疗的独特特征 20 此外，我们最近的结果表明，抗逆转录病毒药物治疗会影响成人海马。 21 神经发生，从而表明暴露于 ARV 的衰老和 AD 大脑的另一个潜在脆弱性。 22 号提案与母公司 R01 拨款直接相关，该拨款也重点关注衰老和 AD 大脑。 23 在具体目标 1 中，我们将确定代表性抗逆转录病毒药物长期治疗对干细胞的影响。衰老和AD模型小鼠海马中的24个细胞和成年神经元在具体目标2中，我们将。 25 确定了受长期暴露于选定抗逆转录病毒药物影响的神经回路的关键共享组件。 26 将生成衰老和 AD 模型小鼠中神经激活的介观全局图，并提供相关的接触 ARV 后的 27 种认知挑战然后我们将逐步选择映射数据集。我们的实验将通过 28 个管道来识别治疗改变的关键大脑和神经回路。 29揭示了抗逆转录病毒药物对海马神经发生的影响，并将为以下作用创建一个电路图空间 30种抗逆转录病毒药物，其上的其他电路图描述了在衰老和衰老的背景下对治疗的各种反应公元31年可以预测和比较。 32 在大量人群中观察到的认知缺陷的普遍存在进一步加剧了这种情况接受 ART 的 HIV-1 感染者的比例。