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: 10426101
• 负责人: Arthur P Arnold
• 金额: $ 55.41万
• 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/10426101
• 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; Institutes; 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; 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; 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疾病的大鼠模型，使研究人员能够 测量保护或加剧疾病的XX和XY性别染色体的差异作用。最多 在男性和女性中，人类疾病的发生不同，表明一种性别受到保护或脆弱 由于两个性别中固有不同的因素。了解保护机制 或脆弱性涉及隔离不同或多或少的保护。性别 染色体（xx vs. xy）是任何类型的细胞中性偏见的一种主要来源，但此类别已是 很难与通常与性染色体补体共同变化的性腺激素作用区分。到 分离和研究性别染色体效应，有必要使实验模型比较XX和XY 具有相同类型的性腺的动物。这些模型尚未适用于研究老鼠的调查人员，但是 刚刚可用。修饰的大鼠有两个基因突变，以引入睾丸确定 基因在非性质的染色体上，并在Y染色体上撞倒。这些修改 用卵巢产生XY和XX大鼠，以及带有睾丸的XX和XY大鼠。该提议是研究新的 开发了遗传改性的大鼠线，以建立两者中和附近的遗传序列的性质 遗传修饰，并确定修饰如何改变卵巢和睾丸的发展。 带有这些修饰的大鼠将与正常大鼠进行比较，以衡量：繁殖生理学， 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模型具有显着优势， 由于它们的规模庞大，有关大鼠基本生理学和性别差异的大量文献，它们 卓越的认知能力和大鼠对特定疾病的研究。成功的大鼠模型将 存放在Rat Resources＆Research Center中，并将其广泛提供给其他研究人员。