Coupling neuroimaging with CLARITY and single cell genomics to dissect sex differences in the developing brain

将神经影像与 CLARITY 和单细胞基因组学结合起来，剖析大脑发育中的性别差异

基本信息

批准号：
10553728
负责人：
Arthur P Arnold
金额：
$ 43.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553728
关键词：
Acrylamides Address Adolescent Affect Age Anatomy Animal Model Area Attention Automobile Driving Autopsy Biological Biology Brain Brain Mapping Brain imaging Brain region Cell Size Cells Collaborations Coupling Data Set Development Disease Dissection Eating Disorders Etiology Female Foundations Genes Genetic Models Genomics Genotype Gonadal Hormones Gonadal Steroid Hormones Gonadal structure Health Histocompatibility Homologous Gene Hormonal Hormones Human Hydrogels Image Impairment Individual Investigation Kallmann Syndrome Knowledge Language Language Development Life Lipids Maps Measures Methods Modeling Molecular Mood Disorders Motor Mus Neuroanatomy Neurobiology Outcome Pathologic Pathway interactions Patients Pattern Ploidies Population Resolution Risk Role Scanning Sex Bias Sex Chromosomes Sex Differences Sex Differentiation Sex Factors Signal Transduction Site Social Development Social Functioning Specific qualifier value Stereotyping Testing Tissue Sample Translating Trisomy United States National Institutes of Health Variant Work Y Chromosome age related analysis pipeline brain magnetic resonance imaging cell type cohort computerized tools density dosage high throughput analysis human model in vivo innovation interdisciplinary collaboration longitudinal analysis male motor control mouse model nervous system disorder neurobehavioral neurodevelopment neuroimaging novel protective effect sex sex chromosome aneuploidy single cell sequencing single-cell RNA sequencing spatiotemporal

项目摘要

Abstract Many neurobehavioral diseases affect females and males differently, and emerge at different stages of life, leading to the conclusion that one sex is protected from diseases by inherent sex factors, such as gonadal hormones and sex chromosomes. The sites and timing of these effects on brain development are unknown. The method of high-throughput high-precision whole-brain MRI imaging has the power to detect such changes with great sensitivity, in both animal models and humans. This project will exploit these powerful methods to separate gonadal hormonal and sex chromosome effects in the mouse model “Sex Chromosome Trisomy” (SCT), at 9 different ages of development, to discover where and when these factors cause sex differences in brain development (Aim 1). The SCT model compares mice with different numbers and types of sex chromosomes (XX, XY, XXY, XYY), each genotype present in gonadal males or females. Then, a novel pipeline of analysis will compare mouse and human brain development at many stages and in informative groups (differing by age, sex, hormonal status, and sex chromosome complement) to determine which changes in mouse brain are also found in humans, in specific brain regions related to different diseases (Aim 2). The analysis will point to changes in mouse brain that model human brain development. These studies will also pinpoint new sex-biasing effects of hormones and sex chromosomes at localized brain regions at specific developmental stages in mice, leading to further investigation of cellular and molecular changes caused by sex at those sites (Aim 3). Cellular effects (cell size, number, density of defined cell populations) of sex-biasing factors will be measured using CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue- hYdrogel). Gene pathways responding to hormonal and sex chromosome effects in individual cell types in specific brain regions will be measured using single cell RNA-seq. These studies, combining high- resolution neuroimaging, CLARITY, and single cell sequencing, will provide a foundation of concepts about where in the brain, and when during development, specific cell populations respond to sex factors, as a prelude for hypothesizing which sex differences underlie the protective effects of sex- biased factors in cells.

抽象的许多神经行为疾病对女性和男性的影响不同，出现的时间也不同。生命的各个阶段，得出这样的结论：固有的性别因素可以保护一种性别免受疾病的影响，例如性腺激素和性染色体这些影响大脑的部位和时间。高通量高精度全脑 MRI 成像方法的进展尚不清楚。在动物模型和人类中以极高的灵敏度检测此类变化的能力。该项目将利用这些强大的方法来分离性腺激素和性染色体的影响在小鼠模型“性染色体三体”（SCT）中，在 9 个不同的发育年龄，发现这些因素在何时何地导致大脑发育的性别差异（目标 1）。比较具有不同数量和类型性染色体（XX、XY、XXY、XYY）的小鼠，每种基因型然后，一种新的分析方法将比较小鼠和人类的性腺。大脑发育的多个阶段和信息群体（因年龄、性别、荷尔蒙状态和性染色体补体）来确定小鼠大脑中的哪些变化也存在于人类中与不同疾病相关的特定大脑区域（目标 2）。分析将指出小鼠的变化。这些研究还将确定新的性别偏见效应。小鼠特定发育阶段局部大脑区域的激素和性染色体，从而进一步研究这些部位由性别引起的细胞和分子变化（目标 3）。性别偏见因素的细胞效应（细胞大小、数量、特定细胞群的密度）将是使用 CLARITY（透明脂质交换丙烯酰胺杂交刚性成像兼容组织）进行测量水凝胶）。响应个体细胞类型中激素和性染色体效应的基因途径。这些研究结合了高水平的研究，将使用单细胞 RNA 测序来测量特定的大脑区域。分辨率神经影像、CLARITY 和单细胞测序将为概念提供基础关于特定细胞群在大脑中的位置以及发育过程中的何时对性做出反应因素，作为假设性别差异是性别保护作用的基础的前奏细胞中的偏见因素。