Innate and Hormone-Mediated Sex Differences in Extracellular Matrix Remodeling

项目总结 生物性别是个人修复和再生组织能力的一个明显因素。女性处于更高的位置 与年龄匹配的男性相比，软组织损伤的风险更高，并表现出更高的退行性疾病发生率 如骨质疏松症、骨质疏松症、骨关节炎和腕管综合征。这些产品的一个共同特点是 退行性疾病是细胞外基质(ECM)动态平衡的破坏。一种微妙的平衡 组织的产生和分解对每个组织的健康功能都是必不可少的。生产过多 基质会导致纤维化，而过度的基质分解会导致组织功能减弱。然而， 生物性在ECM动态平衡过程中所起的作用目前尚不清楚。一项基本原则 了解基于性别的组织重塑差异，以及性别对这一过程的调节 激素信号转导，对于理解损伤和疾病的差异以及建立患者- 具体的再生策略。我们研究计划的总体目标是了解 生物性调节细胞外基质重塑的过程，从最初的机械转导到信号 加工到ECM合成。主题1：雄性细胞和雌性细胞感觉到它们的局部机械环境吗？ 不同？在许多组织中有证据表明，ECM的结构、组织和所产生的功能不同 在年龄匹配的男性和女性之间。然而，这对细胞生物学的影响目前尚不清楚。 定制的和商用的生物反应器将被用来识别传感和细胞- 仅基于生物性别(分离的细胞)和当地环境的对机械刺激的水平反应 (外植体组织和工程微环境)。主题2：是母体生产和生产的平衡 因生理性别而改变的崩溃？因为退行性疾病依赖于 为了更好地理解细胞外基质的合成和降解，需要一种广谱的方法来了解细胞外基质的重塑。vbl.使用 建立了机械驱动的ECM重塑模型，我们可以评估ECM分子的合成 和ECM降解酶，以及实时检测ECM分解的产物。这些技术 将允许实时了解ECM周转的整体情况。主题3：性激素的存在如何 影响与细胞外基质重塑相关的细胞信号通路？ECM结构在以下方面发生了巨大变化 怀孕显然表明激素信号在细胞外基质重塑中起着重要作用，研究 显示雌激素信号在肌肉骨骼和心脏组织中的重要作用。使用自定义- 设计的流体交换生物反应器，我们将精确控制性行为的浓度和持续时间 荷尔蒙暴露以及局部机械环境的同时，使我们能够研究 雌激素和孕激素信号在重塑过程不同阶段的作用。这些研究将 使人们能够从根本上理解生物性别对组织修复能力的贡献，并为 为我们的新型体外工具确定新的靶点，以开发针对患者的治疗方法。

PROJECT SUMMARY Biological sex is a clear factor in an individual’s ability to repair and regenerate tissue. Females are at higher risk for soft tissue injuries compared to age-matched males and exhibit higher rates of degenerative diseases such as osteoporosis, sarcopenia, osteoarthritis, and carpal tunnel syndrome. One common hallmark of these degenerative diseases is the disruption in homeostasis of the extracellular matrix (ECM). A delicate balance in tissue production and breakdown is essential to healthy function in every single tissue. Production of too much matrix can lead to fibrosis, while excessive matrix breakdown results in weakened tissue function. However, the role that biological sex plays in the processes of ECM homeostasis are currently unknown. A fundamental understanding of sex-based differences in tissue remodeling, and the regulation of this process by sex hormone signaling, will be critical to understanding divergence in injury and disease and establishing patient- specific regenerative strategies. The overall goal of our research program is to understand how biological sex regulates the process of ECM remodeling, from initial mechanotransduction to signal processing to ECM synthesis. Theme 1: Do male and female cells sense their local mechanical environment differently? There is evidence in many tissues that ECM structure, organization, and resulting function differs between age-matched males and females. However, the effect this has on cell biology is currently unknown. Custom-built and commercially available bioreactors will be used to identify differences in the sensing and cell- level responses to mechanical stimuli based on biological sex alone (isolated cells) and the local environment (explant tissue and engineered microenvironments). Theme 2: Is the balance of matrix production and breakdown altered by biological sex? Since degenerative diseases rely on a disruption of the balance between synthesis and degradation, a broad-spectrum approach to understanding ECM remodeling is necessary. Using an established model of mechanically-driven ECM remodeling, we can assess synthesis of ECM molecules and ECM-degrading enzymes, as well as detect products of ECM breakdown in real time. These techniques will allow for a whole picture of ECM turnover in real time. Theme 3: How does the presence of sex hormones affect cell signaling pathways associated with ECM remodeling? Dramatic changes in ECM structure during pregnancy clearly point to a substantial role for hormone signaling in ECM remodeling, and studies demonstrate a significant role for estrogen signaling in musculoskeletal and cardiac tissues. Using custom- designed fluid exchange bioreactors, we will have precise control over the concentration and duration of sex hormones exposure as well as the local mechanical environment simultaneously, allowing us to study the effect of estrogen and progesterone signaling in different phases of the remodeling process. These studies will enable a fundamental understanding of the contribution of biological sex to tissue repair capacity and pave the way for our novel in vitro tools to identify new targets for the development of patient-specific therapeutics.