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.

Narrative XX and XY sex chromosomes cause sex difference in disease, because of genes that protect or harm one sex more than the other. The current project develops new genetically modified rats in which the effects of sex chromosomes can be measured in animals that have the same type of gonad. The rats will be widely used in rat models of disease, to establish molecular mechanisms leading to sex differences in protection from disease.