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雄性的影响不同，并在不同的生活阶段，得出结论，即一种性别受到固有的性因素保护疾病，例如性腺激素和性染色体。这些对大脑的影响的位点和时间和时间发展是未知的。高通量高精度全脑MRI成像的方法具有在动物模型和人类中，都以极大的敏感性来检测这种变化的力量。这项目将探索这些强大的方法来分开性腺激素和性染色体效应在老鼠模型“性别染色体三体”（SCT）中，在9个不同年龄的开发年龄，以发现这些因素的何时以及何时导致大脑发育的性别差异（AIM 1）。 SCT模型将小鼠与不同数量和类型的性染色体（XX，XY，XXY，XYY）进行比较出现在性腺雄性或女性中。然后，新的分析管道将比较小鼠和人类在许多阶段和信息群体中的大脑发展（因年龄，性别，荷尔蒙地位而有所不同，并且性别染色体的完成），以确定人类在人类中也发现了哪些变化，与不同疾病有关的特定大脑区域（AIM 2）。分析将指出鼠标的变化大脑对人脑发育进行建模。这些研究还将指出小鼠特定发育阶段的局部大脑区域的骑马和性染色体，导致进一步研究这些位点性别引起的细胞和分子变化（AIM 3）。性别偏见因素的细胞效应（细胞大小，数量，定义细胞群体的密度）为使用清晰度测量（清晰的脂质交换的丙烯酰胺杂交刚性成像组织 - 水凝胶）。基因途径响应各个细胞类型的激素和性染色体作用在特定的大脑区域中，将使用单细胞RNA-seq进行测量。这些研究，结合了高分辨率神经影像学，清晰度和单细胞测序将为概念提供基础关于大脑中的位置以及在发育期间，特定细胞种群对性别做出反应因素，作为假设哪些性别差异的前奏细胞中的偏置因子。