Engineering Biomaterial Properties to Modulate Adipocyte Phenotype

在美国，被归类为肥胖的人数几乎占总人口的50%，而且这个数字预计还会上升。肥胖会导致脂肪组织持续发炎，而这种发炎会增加心脏病、2型糖尿病和中风等疾病的风险因素。尽管肥胖越来越流行，但人们对细胞外的支持物质如何影响脂肪细胞的疾病状态的了解有限。本项目研究组织成分和硬度对脂肪细胞对炎症的贡献反应的影响。这一知识将使研究小组能够制造组织模拟物，用于开发治疗肥胖和炎症的疗法。这项研究将用于从代表性不足的群体中招募学生，并将提供生物学、生物化学和材料工程方面的多学科培训。拓展活动包括为参加普渡大学女性工程项目的女高中生开发新的实验室模块。在肥胖期间，肥厚脂肪细胞分泌促炎细胞因子，可引起细胞外基质（ECM）的变化，并导致一系列疾病。最近的研究表明，ECM的组成可用于导致正常脂肪细胞转变为病变表型。相反，ECM可用于挽救脂肪细胞功能障碍并将其恢复到健康表型。本文所述的实验将检验ECM的生化组成和生物物理特性之间的相互作用及其对脂肪细胞功能障碍的影响。该研究首先定义了透明质酸对肥胖相关脂肪细胞功能障碍的影响（目的1）。接下来，将确定应力松弛和僵硬对脂肪细胞功能障碍的影响（目标2）。最后，将评估配体诱导的贪婪度、应力松弛和僵硬度对脂肪细胞功能障碍的相互作用，以了解每个因素所起的加权贡献（目标#3）。总之，这项工作将显示微环境的变化如何提供指导脂肪细胞功能的线索，并将建立一个明确的模型来更好地理解肥胖的驱动因素。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The number of people in the US that are classified as obese is almost 50% of the population, and that number is expected to rise. Obesity contributes to a state of continuous inflammation in fat tissue, and this inflammation increases the risk factor for conditions such as heart disease, type 2 diabetes, and stroke. Although there is a growing epidemic of obesity, there is limited understanding of how the support material outside of the cell affects the disease state of fat cells. This project investigates the effect of the tissue components and stiffness on the contributing response of fat cells toward inflammation. This knowledge will allow the team of investigators to make tissue mimics that can be used to develop therapies to treat obesity and the inflammation that occurs. This research will be used to recruit students from underrepresented groups and will provide multidisciplinary training in biology, biochemistry, and materials engineering. Outreach activities include developing new laboratory modules for female high school students who attend programs hosted by the Women in Engineering Program at Purdue University. During obesity, hypertrophic adipocytes secrete pro-inflammatory cytokines that can cause changes in the extracellular matrix (ECM) and contribute to a host of disease conditions. Recent studies show that the composition of the ECM can be used to cause normal adipocytes to transition into a diseased phenotype. Conversely, the ECM can be used to rescue adipocyte dysfunction and revert them to a healthy phenotype. Experiments described herein will examine the interactions between the biochemical composition and the biophysical properties of the ECM and their effect on adipocyte dysfunction. The research begins by defining the effect that hyaluronic acid avidity has on obesity-related adipocyte dysfunction (Objective #1). Next, the effect that stress relaxation and stiffness have on adipocyte dysfunction will be determined (Objective #2). Finally, the interplay between ligand-induced avidity, stress relaxation, and stiffness have on adipocyte dysfunction will be evaluated in order to understand the weighted contribution that each factor plays (Objective #3). Taken together, this work will show how changes in the microenvironment provide cues that guide adipocyte function and will establish a defined model to better understand drivers of obesity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.