Biomaterial Models of Ancestral Contributions to Wound Healing

项目摘要 非洲血统的人患上疤痕组织过度生长或瘢痕疙瘩的可能性是普通人的7倍 欧洲血统的。纤维化、慢性炎症和过度的疤痕形成是由个人的 祖传背景。血统，通过自我认同的三个组成部分在我们的工作中量化，基因 血统和社会文化经历会影响伤口愈合。虽然我们知道祖先的影响 临床伤口愈合，我们不了解祖先是如何影响细胞功能或细胞间通讯的 在伤口反应中。了解祖先对细胞功能的贡献是询问创伤的关键 弥合分歧。我们假设祖先会通知伤口细胞反应的不同 治愈。我们研究计划的总体目标是利用生物材料模型来询问祖先 在伤口愈合方面的贡献。在这项工作中，我们将询问单核细胞先天免疫细胞和CD34+ 祖细胞干细胞。我们提出的研究计划将回答三个关键问题：1)祖先是如何 会影响细胞生理学吗？我们小组的初步工作表明，在 分离的外周血单核细胞比较自我认同的非洲人和欧洲人的后代。至 鉴定祖先成分超越自我认同，我们将询问遗传祖先和社会文化 量化祖先的因素。为了确定每个祖先成分如何影响细胞功能，我们将 与机械抑制剂一起进行RNA测序和蛋白质组学方法以评估细胞 单核细胞和祖细胞干细胞的功能差异。2)祖先是如何影响细胞的 表型？虽然非洲血统与疤痕形成增加有关，但之前的临床研究没有 提供对伤口部位发生的细胞表型的机械性见解。为了解决这一限制， 我们将利用生物材料和可溶性因子来模拟伤口细胞外基质环境。要确定 祖细胞成分如何影响下列细胞表型、单核细胞和祖细胞干细胞反应 进入生物材料微环境的培养将被量化。3)血统如何与 伤口愈合中的细胞反应？创伤反应需要细胞间的交流。我们将利用 细胞-细胞相互作用的生物材料模型和通过氧化应激损伤模拟创伤。我们将评估 在这些创伤环境中，祖先是如何通过遗传和分泌组影响细胞间的通讯的 表情。这项ESI-MIRA将使我的团队能够通过以下方式衡量祖先对伤口愈合的影响 生物材料平台的操纵。归根结底，我实验室研究的愿景是辨别影响 关于伤口愈合差异的祖先和利用生物材料模型来调查健康状况 愈合方面的差异。

PROJECT ABSTRACT People of African ancestry are 7X more likely to develop overgrowth of scar tissue, or keloids, compared people of European ancestry. Fibrosis, chronic inflammation, and excessive scar formation is dictated by an individual’s ancestral background. Ancestry, quantified in our work through three components of self-identification, genetic ancestry, and sociocultural experiences, informs wound healing. While it is known that ancestry influences clinical wound healing, we do not understand how ancestry influences cell function or cell to cell communication in the wound response. Understanding ancestral contributions to cellular function is critical to interrogate wound healing differences. We hypothesize that ancestry informs differences in cellular response in wound healing. The overall goal of our research program is to leverage biomaterial models to interrogate ancestral contributions in wound healing. In this work, we will interrogate monocyte innate immune cells and CD34+ progenitor stem cells. Our proposed research program will answer three key questions: 1) How does ancestry influence cellular physiology? Preliminary work in our group demonstrates gene expression differences in isolated peripheral blood mononuclear cells comparing self-identified African vs. European descendants. To identify ancestral components beyond self-identification, we will interrogate genetic ancestry and sociocultural factors to quantify ancestry. To determine how each ancestral component influences cell function, we will conduct RNA sequencing and proteomic methodologies in tandem with mechanistic inhibitors to assess cell function differences in monocytes and progenitor stem cells. 2) How does ancestry influence cellular phenotype? While African ancestry is correlated with elevated scar formation, previous clinical studies do not provide mechanistic insights into cellular phenotype that occurs within wound sites. To address this limitation, we will leverage biomaterials and soluble factors to mimic wound extracellular matrix environments. To determine how ancestral components influences the cell phenotype, monocyte and progenitor stem cell responses following culture into the biomaterial microenvironments will be quantified. 3) How does ancestry correlate with the cellular response in wound healing? Wound responses necessitate cell to cell communication. We will utilize biomaterial models of cell-cell interaction and simulate wounding through oxidative stress injury. We will assess how ancestry influences cell to cell communication in these wound environments via genetic and secretome expression. This ESI-MIRA will enable my group to measure the influence of ancestry on wound healing through manipulation of biomaterial platforms. Ultimately, the vision for my lab’s research is to discern the impact of ancestry on wound healing differences and leverage biomaterial models to investigate health disparities in healing.