Transformative rat models to study sex differences in disease

项目摘要 长期目标是开发和验证老鼠的疾病模型，使研究人员能够 测量XX和XY性染色体保护或加重疾病的不同作用。多数 人类疾病在男性和女性中发生的情况不同，这表明一种性别受到保护或易受伤害。 这是因为两性天生不同的因素所致。了解保护机制 或者，脆弱性涉及隔离不同的分子途径，造成或多或少的保护。性 染色体(XX对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 很难与性腺激素效应区分开来，性激素效应往往与性染色体互补共同变化。至 分离和研究性染色体效应，有必要制作XX和XY比较的实验模型 性腺类型相同的动物。研究老鼠的研究人员还没有得到这样的模型，但 才刚刚开始供应。改造后的大鼠有两个基因突变，以引入睾丸决定 基因Sry在一个非性染色体上，并在Y染色体上敲除Sry。这些修改 用卵巢制作XY和XX大鼠，用睾丸制作XX和XY大鼠。这项建议是为了研究新的 开发转基因大鼠品系，以确定这两个品系及其附近的遗传序列的性质 基因修饰，并确定这些修饰如何改变卵巢和睾丸的发育。 携带这些修饰的大鼠将与正常大鼠进行比较，以测量：生殖生理， 大脑的性发育，心脏功能，全身和肺高压，以及高血压- 相关的认知功能。大鼠作为人类生理和疾病的模型提供了显著的优势， 由于它们的体型很大，关于老鼠的基本生理学和性别差异的大量文献，他们的 优越的认知能力，以及大鼠研究特定疾病的适合性。成功的大鼠模型将 存放在老鼠资源和研究中心，并向其他研究人员广泛提供。

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.