Brain-wide screen for a neural pacemaker of aging

全脑筛查衰老神经起搏器

基本信息

批准号：
10207466
负责人：
ANNE BRUNET
金额：
$ 265.91万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207466
关键词：
Address Adult African Age Aging Alzheimer&apos s Disease Automobile Driving Behavior Biology Biosensor Brain Brain region Brain scan Calcium Cell physiology Cells Characteristics Chronic Disease Cognitive Custom Data Data Set Disease Fiber Genetic Genomics Goals Health Health Status Human Image Imaging Techniques Impaired cognition Individual Intervention Killifishes Knowledge Larva Lead Light Longevity Longitudinal Studies Mammals Measures Memory Loss Metabolic Metabolism Metformin Modeling Molecular Profiling Monitor Mus Nature Neurodegenerative Disorders Neurons Neurophysiology - biologic function Opsin Organ Organism Pacemakers Pattern Peripheral Photometry Play Population Process Proteomics Reporting Rest Ribosomes Risk Factors Role Signal Transduction Synaptic Transmission System Technology Therapeutic Time Tissues United States Vascular Dementia Vertebrates Vision Whole Organism Work Youth Zebrafish age related aging brain base biological systems cognitive ability design genome editing improved in vivo innovation knowledge of results life history molecular phenotype mortality neuronal circuitry neuroregulation novel novel strategies optogenetics relating to nervous system response tool

项目摘要

Summary Aging is a gradual process that results in the loss of cellular function across the body, leading to numerous chronic diseases that promote mortality. Elucidating the precise mechanisms of aging is critical for reducing illness and extending healthy lifespan. However, almost every tissue in the body is modified by aging, making it difficult to pinpoint the principal controller of aging. The goal of this proposal is to determine whether the brain modulates aging through coordinated activity patterns within discrete neuronal networks. We will use one of the shortest-living vertebrates, the African turquoise killifish, as a rapid, high-throughput model of aging to uncover genetically- defined neurons that regulate cellular metabolism and lifespan. Employing large-scale light-sheet imaging in killifish, we will visualize brain-wide calcium activity dynamics to unbiasedly identify neurons that respond to longevity interventions. We will characterize the genetic profiles of the identified neurons via a combination of immunohistochemical, single cell, and phosphorylated ribosome capture approaches. To examine whether these neurons play a causal role to control overall cellular function in the brain and other tissues, we will optogenetically activate these neurons and measure molecular signatures of youth and in vivo metabolic activity in the brain and peripheral tissues. We will monitor and manipulate neural activity throughout the short lifespan of killifish using fiber photometry to determine if this ‘neural pacemaker’ dictates the tempo of aging and youthful behavior. These approaches will then be extended to longer-lived species – zebrafish and mice. Knowledge resulting from these studies should be transformative to understand the fundamental mechanisms that regulate and synchronize aging and longevity. As age is the prime risk factor for many diseases, including neurodegenerative diseases, this proposal should provide new, circuit-based approaches to treat these diseases. !

概括衰老是一个成绩过程，导致整个体内细胞功能的丧失，导致许多促进死亡率的慢性疾病。阐明精度衰老的机制对于减少疾病和延长健康寿命至关重要。但是，体内几乎所有组织都通过衰老来修饰，这使得很难查明衰老的主要控制器。该提议的目的是确定大脑是否通过离散的协调活动模式调节衰老神经元网络。我们将使用最短的脊椎动物之一，非洲人绿松石Killifish，是一种快速，高通量的衰老模型，以发现一般 - 定义调节细胞代谢和寿命的神经元。使用大规模在Killifish中的灯页成像，我们将可视化大脑范围的钙活性动态公正地识别对寿命干预措施做出反应的神经元。我们将表征通过免疫组织化学的结合，鉴定出神经元的遗传特征单细胞和磷酸化的核糖体捕获方法。检查是否这些神经元在控制大脑和其他的整体细胞功能方面起着因果作用组织，我们将在光源上激活这些神经元并测量分子青年和体内代谢活性在大脑和周围组织中的特征。我们将在整个Killifish的寿命中监测和操纵神经活动纤维光度法确定此“神经起搏器”是否决定了衰老的速度年轻的行为。这些方法将扩展到寿命长的物种 - 斑马鱼和老鼠。这些研究产生的知识应具有变革性了解调节和同步衰老的基本机制长寿。由于年龄是许多疾病的主要危险因素，包括神经退行性疾病，该提案应提供基于电路的新方法来治疗这些方法疾病。呢