Innate and Hormone-Mediated Sex Differences in Extracellular Matrix Remodeling

项目摘要 生物性别是个体修复和再生组织能力的一个明显因素。女性在更高的 与年龄匹配的男性相比， 例如骨质疏松症、肌肉减少症、骨关节炎和腕管综合征。其中一个共同的标志是 退行性疾病是细胞外基质（ECM）稳态的破坏。一种微妙的平衡， 组织的产生和分解对于每个组织的健康功能是必不可少的。生产过多 基质可导致纤维化，而过度的基质分解导致组织功能减弱。然而，在这方面， 生物性别在ECM稳态过程中的作用目前尚不清楚。一项基本 了解组织重塑中基于性别的差异，以及性别对这一过程的调节 激素信号，将是至关重要的理解分歧，在损伤和疾病，并建立病人- 具体的再生策略。我们研究计划的总体目标是了解 生物性别调节ECM重塑的过程，从最初的机械传导到信号传导 加工到ECM合成。主题1：雄性和雌性细胞是否感知到它们局部的机械环境 不同吗有证据表明，在许多组织中，ECM的结构，组织和功能不同 年龄匹配的男性和女性之间的差异。然而，这对细胞生物学的影响目前尚不清楚。 定制的和商业上可获得的生物反应器将用于识别传感和细胞- 对机械刺激的水平反应仅基于生物性别（孤立细胞）和局部环境 （外植体组织和工程化微环境）。主题2：矩阵生产和 会被生理性别改变吗由于退行性疾病依赖于破坏 合成和降解，一个广谱的方法来理解ECM重塑是必要的。使用 建立机械驱动ECM重塑的模型，我们可以评估ECM分子的合成 和ECM降解酶，以及真实的时间检测ECM分解的产物。这些技术 将允许在真实的时间内对ECM的周转情况进行全面了解。主题3：性激素的存在如何 影响与ECM重塑相关的细胞信号通路？2000年期间ECM结构的巨大变化 妊娠明确指出激素信号在ECM重塑中的重要作用， 证明了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，我们将有精确的控制浓度和持续时间的性别 激素暴露以及当地的机械环境，使我们能够研究 雌激素和孕激素信号在重塑过程的不同阶段的作用。这些研究将 使人们能够从根本上了解生物性别对组织修复能力的贡献， 我们的新的体外工具，以确定新的目标，为发展患者特异性治疗的方式。

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.