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艾滋病毒年龄较大的人口，部分原因是抗逆转录病毒的效率 4疗法（ART）可显着改善感染者的预期寿命。这个老龄化的人口 5不可避免地面临着包括阿尔茨海默氏病（AD）在内的神经退行性疾病的风险。 6这些担忧是 7这些定义可能仅由于HIV-1感染。 8但是，这也可能表明长期艺术本身有助于损害。后者的可能性是 9特别关心的是，越来越多的未感染的个人员工使用抗逆转录病毒（ARV）为 10预防前预防（PREP）。艺术引起的变化及其对大脑的影响的机制 11可能会受到延长治疗ARV影响的电路尚不清楚；关于动作的知之甚少衰老和ad养大脑中的12个ARV。艺术引起的变化和大脑电路的机制 13可能会受到延长ARV治疗的影响尚不清楚；关于动作的知之甚少 14个ARV在衰老和AD伴脑中的大脑中。 15我们建议将最近开发的新工具应用于分析神经发生和 16构造，比较和分析小鼠脑中神经元激活的3D全脑图以揭示 17由代表ARV影响的关键神经回路。我们的假设是神经元的3D模式 18暴露于ARV并参与挑战行为任务的衰老和AD模型动物的激活可以 19两者都揭示了定义这些效果的关键电路，并作为治疗方法的独特特征 20效果。此外，我们最近的结果表明，用ARV治疗会影响成年海马 21神经发生，因此表明了暴露于ARV的衰老和AD脑的另一个潜在脆弱性。这 22提案与父级R01赠款直接相关，后者也侧重于衰老和广告大脑。 23在特定目标1中，我们将确定用代表性ARV对茎的长时间处理的影响衰老和AD模型小鼠海马中的24个细胞和成年神经元。在特定的目标2中，我们将 25确定受长期暴露于某些ARV影响的神经回路的关键共享组件。我们 26将产生与相关的衰老和AD模型小鼠中神经元激活的介观全球图 27接触ARV后的认知挑战。然后，我们将对映射数据集进行逐步选择 28管道以确定治疗方法改变的关键大脑区域和神经回路。我们的实验会 29揭示了ARV对海马神经发生的影响，并将创建一个电路映射空间以进行动作 30其他电路图在衰老和衰老的背景下描述了对治疗的各种反应的ARV 31 AD可以投影和比较。 32 在实质性的认知缺陷中的普遍性进一步加剧了正在接受艺术的HIV-1感染者的比例。