Biomaterial technologies for interrogating sex differences in tissue repair and homeostasis

项目摘要 一个人的生理性别会显著影响他们修复和再生组织的能力。的一个明显例子 这是妇女在绝经后愈合和再生新的健康组织的能力降低， 性激素信号的严重缺失这种激素水平的降低不成比例地增强了 许多退行性疾病的风险，包括骨质疏松症，骨关节炎，心血管疾病， 组织分解速度超过组织修复速度的退行性脑部疾病。虽然 已知有几个因素导致组织修复中的性别差异，包括生物力学，营养， 身体活动水平和性激素，这些参数之间的相互作用还没有得到很好的理解。 具体来说，目前尚不清楚原生性别在组织结构上的差异以及由此产生的差异。 机械功能决定细胞表型和行为，以及这种作用如何与雌激素信号相互作用， 整体控制组织修复。因此，一个基本的，机械的理解细胞如何响应 空间和机械的线索，同时介导雌激素信号是至关重要的，以了解为什么 性别差异发生在组织修复和稳态以及未来以患者为中心的修复和再生方面 战略布局我们研究计划的总体目标是开发生物材料工具来询问性别 组织修复和体内平衡的差异。主题1：男性和女性MSC对空间和 细胞微环境的机械特性不同吗？许多组织中有证据表明 细胞外基质的结构、组织和功能在年龄匹配的男性之间存在差异， 女性然而，没有研究表明这如何影响细胞反应。生物材料设计模仿 结构胶原的纤维性质和蛋白聚糖的粘弹性性质在天然的 细胞外基质将用于评估细胞对基质受控变化反应的性别差异。 特性.主题2：雌激素如何呈递给细胞影响下游转录和行为？ 虽然已知雌激素在细胞过程中起作用，但这些结果取决于浓度， 雌激素在细胞中的暂时呈现。为了解决这一限制，我们将使用浓度梯度 发生器微芯片，以快速准确地确定雌激素浓度和时间对细胞的影响， 转录活性主题3：我们能否设计生物材料系统来控制释放和呈现 雌激素对细胞的影响释放速率在数小时至数月的范围内，将通过调节扩散来控制 通过材料化学和建筑学来研究生物材料。控制释放速率和定位的能力 在体内的特定组织是至关重要的，以促进该网站的雌激素效应，同时减少负面影响， 和潜在的致命脱靶效应这些研究的结果将提供未来的研究途径， 了解雌激素和细胞微环境如何驱动干细胞行为的性别差异， 对组织修复和体内平衡至关重要。

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.