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Biomaterial technologies for interrogating sex differences in tissue repair and homeostasis

用于探究组织修复和稳态中性别差异的生物材料技术

基本信息

批准号：
10277013
负责人：
Jennifer Lindsey Robinson
金额：
$ 37.08万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10277013
关键词：
Address Affect Age Architecture Behavior Biocompatible Materials Biomechanics Brain Diseases Cardiovascular Diseases Cell physiology Cells Chemistry Collagen Cues Degenerative Disorder Degenerative polyarthritis Development Diffusion Engineering Environment Estrogens Extracellular Matrix Female Future Genetic Transcription Goals Gonadal Steroid Hormones Homeostasis Hormones Hour Individual Libido Mechanics Mediating Menopause Natural regeneration Osteoporosis Patients Phenotype Physical activity Play Property Proteoglycan Research Risk Role Sex Differences Signal Transduction Site Structure System Technology Tissues Woman Work biological sex cell behavior design healing hormonal signals individualized medicine male mechanical properties men mesenchymal stromal cell microchip nutrition patient oriented programs repaired response sex stem cells tissue regeneration tissue repair tool viscoelasticity

项目摘要

PROJECT SUMMARY An individuals’ biological sex significantly affects their ability to repair and regenerate tissue. A clear example of this is the reduced ability for women to heal and regenerate new, healthy tissue after menopause, which results from a significant loss of sex hormone signaling. This reduction in hormone levels disproportionately enhances the risk for many degenerative diseases including osteoporosis, osteoarthritis, cardiovascular disease, and degenerative brain diseases in which the rate of tissue breakdown exceeds the rate of tissue repair. While it is known that several factors contribute to sex differences in tissue repair including biomechanics, nutrition, physical activity level and sex hormones, the interplay between these parameters is not well understood. Specifically, it is unknown how the native sex differences in tissue structure and the resulting differences in mechanical function dictate cell phenotype and behavior and how this effect interacts with estrogen signaling to overall control tissue repair. Thus, a fundamental, mechanistic understanding of how a cell responds to the spatial and mechanical cues of its environment while mediating estrogen signaling is critical to understand why sex differences occur in tissue repair and homeostasis and for future patient-centered repair and regeneration strategies. The overall goal of our research program aims to develop biomaterial tools to interrogate sex differences in tissue repair and homeostasis. Theme 1: Do male and female MSCs respond to spatial and mechanical properties of the cell microenvironment differently? There is evidence in many tissues that extracellular matrix structure, organization, and resulting function differs between age-matched males and females. However, there are no studies showing how this affects cell response. Biomaterials engineered to mimic both the fibrous properties of structural collagens and the viscoelastic properties of proteoglycans in the native extracellular matrix will be used to assess sex differences in cell response to controlled changes in matrix properties. Theme 2: How does estrogen presentation to the cell affect downstream transcription and behavior? While estrogen is known to play a role on cell processes, these results are dependent on the concentration and the temporal presentation of estrogen to the cell. To address this limitation, we will use concentration gradient generator microchips to quickly and accurately determine the effect of estrogen concentration and timing on cell transcriptional activity. Theme 3: Can we engineer biomaterial systems to control release and presentation of estrogen to the cells? Release rates in a range of hours to months will be controlled by modulating diffusion out of the biomaterials via material chemistry and architecture. The ability to control the rate of release and localize to a specific tissue in the body is critical to promote the estrogen effects at the site while reducing the negative and potentially deadly off-target effects. Results from these studies will provide future avenues of study to understand how estrogen and the cell microenvironment drive sex differences in stem cell behavior which is critical for tissue repair and homeostasis in both women and men.

项目总结