Transformative rat models to study sex differences in disease

研究疾病性别差异的转化大鼠模型

• 批准号: 10596153
• 负责人: Arthur P Arnold
• 金额: $ 56.71万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596153
• 关键词: Address; Adrenal Glands; Adult; Aging; Alzheimer' s Disease; Animal Experimentation; Animals; Applications Grants; Autoimmune Diseases; Backcrossings; Behavioral; Biological; Biological Factors; Biomedical Research; Brain; Breeding; Cardiovascular Diseases; Cardiovascular Physiology; Categories; Cells; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; DNA Sequence Alteration; Deposition; Development; Disease; Disease model; Embryo; Estrous Cycle; Experimental Models; Fathers; Female; Fertility; Four Core Genotypes; Funding; Gene Expression; Genes; Genetic; Genomics; Gonadal Hormones; Gonadal structure; Growth; Histology; Hypertension; Incidence; Kidney; Left; Literature; Lung diseases; Malignant Neoplasms; Measures; Mission; Modeling; Modification; Molecular; Mus; Mutation; Nature; Neurodegenerative Disorders; Obesity; Ovary; Pathway interactions; Physiology; Ploidies; Population; Puberty; Publishing; Pulmonary Hypertension; Rat Transgene; Rattus; Reproducibility; Reproduction; Reproductive Physiology; Research; Research Personnel; Resources; Sea; Sex Behavior; Sex Bias; Sex Chromosomes; Sex Differences; Sexual Development; Site; Source; Specificity; Sprague-Dawley Rats; Stroke; System; Systemic hypertension; Testis; Tissues; Transgenes; Transgenic Organisms; United States National Institutes of Health; Y Chromosome; autosome; brain morphology; cell type; cognitive ability; cognitive function; dosage; gonad development; heart function; human disease; human model; male; mouse model; mutant; new therapeutic target; offspring; programs; protective factors; sex; sexual dimorphism; sry Genes; tool

Project Summary The long-term objectives are to develop and validate rat models of disease that allow investigators to measure the differential effects of XX and XY sex chromosomes that protect from or exacerbate disease. Most human diseases occur differently in males and females, indicating that one sex is protected or vulnerable because of factors that are inherently different in the two sexes. Understanding the mechanisms of protection or vulnerability involves isolating different molecular pathways causing greater or less protection. Sex chromosomes (XX vs. XY) are one major source of sex bias within any type of cell, but this category has been difficult to discriminate from gonadal hormone effects that often co-vary with sex chromosome complement. To isolate and study sex chromosome effects, it is necessary to make experimental models comparing XX and XY animals with the same type of gonad. Such models have not been available to investigators who study rats, but have just become available. The modified rats have two genetic mutations, to introduce the testis-determining gene Sry onto a non-sex-chromosome, and to knock Sry out on the Y chromosome. These modifications produce XY and XX rats with ovaries, and XX and XY rats with testes. The proposal is to study the newly developed genetically modified rat lines, to establish the nature of genetic sequence in and near the two genetic modifications, and to determine how the modifications change the development of ovaries and testes. Rats bearing these modifications will be compared to normal rats, to measure: physiology of reproduction, sexual development of the brain, cardiac function, systemic and pulmonary hypertension, and hypertension- related cognitive function. Rats offer significant advantages as models of human physiology and disease, because of their large size, the large literature concerning basic physiology and sex differences in rats, their superior cognitive ability, and suitability of rats to research on specific diseases. The successful rat models will be deposited in the Rat Resources & Research Center and made widely available to other investigators.

项目摘要 长期目标是开发和验证大鼠疾病模型，使研究人员能够 测量XX和XY性染色体的不同影响，防止或加重疾病。最 人类疾病在男性和女性中的发生率不同，表明一种性别受到保护或易受伤害 这是因为两性之间存在固有的差异。了解保护机制 或脆弱性涉及隔离不同的分子途径，从而产生或多或少的保护。性 染色体（XX与XY）是任何类型细胞中性别偏见的一个主要来源，但这一类别一直是 很难与性腺激素的作用区分开来，性腺激素的作用通常与性染色体的互补性共同变化。到 分离和研究性染色体效应，有必要建立比较XX和XY的实验模型 具有相同类型性腺的动物。研究老鼠的研究人员还没有得到这样的模型， 刚刚有空。改良的老鼠有两个基因突变，引入睾丸决定 将Sry基因植入非性染色体，并将Y染色体上的Sry基因敲除。这些修改 产生具有卵巢的XY和XX大鼠，以及具有睾丸的XX和XY大鼠。建议是研究新的 开发了转基因大鼠品系，建立了两种基因序列的性质及其附近， 基因修饰，并确定修饰如何改变卵巢和睾丸的发育。 将携带这些修饰的大鼠与正常大鼠进行比较，以测量：生殖生理学， 大脑的性发育、心脏功能、全身性和肺动脉高压以及高血压- 相关的认知功能。大鼠作为人类生理学和疾病的模型具有显著的优势， 由于它们的体积大，关于大鼠的基本生理学和性别差异的大量文献， 上级认知能力，以及大鼠对特定疾病研究的适用性。成功的大鼠模型将 保存在老鼠资源和研究中心，并广泛提供给其他研究人员。