Transformative rat models to study sex differences in disease

项目概要 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 性染色体在预防或加剧疾病方面的不同作用。大多数 人类疾病在男性和女性中的发生情况不同，表明一种性别受到保护或脆弱 因为两性的因素本质上是不同的。了解保护机制 或脆弱性涉及隔离不同的分子途径，从而导致或多或少的保护。性别 染色体（XX 与 XY）是任何类型细胞内性别偏见的一个主要来源，但这一类别已被 很难区分性激素的影响，而性激素的影响通常与性染色体补体共同变化。至 分离和研究性染色体效应，需要制作比较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尚未获得此类模型，但 刚刚可用。改造后的老鼠有两个基因突变，以引入决定睾丸的功能 基因 Sry 到非性染色体上，并在 Y 染色体上敲除 Sry。这些修改 产生带有卵巢的 XY 和 XX 大鼠，以及带有睾丸的 XX 和 XY 大鼠。建议研究新的 开发了转基因老鼠品系，以确定这两种老鼠内部及其附近的基因序列的性质 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：生殖生理学、 大脑的性发育、心脏功能、全身性高血压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的优势， 由于它们的体型较大，有关大鼠基本生理学和性别差异的大量文献，它们的 大鼠具有优越的认知能力，适合研究特定疾病。成功的大鼠模型将 存放在大鼠资源与研究中心，并广泛提供给其他研究人员。

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.