Transformative rat models to study sex differences in disease

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.

Grant Number: 5R01OD030496-05
NIH Institute/Center: NIH
Principal Investigator: Arthur Arnold