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: 10180448
• 负责人: Arthur P Arnold
• 金额: $ 60.74万
• 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/10180448
• 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.

项目总结