Defining the role of mutational burden in sustaining normal homeostasis during aging

项目摘要 皮肤是由三个主要层组成的动态器官，最顶层是 上皮，然后是基底膜和真皮。皮肤内的干细胞 位于基底层内，基底层是上皮的最内层。在这一层之下 基底膜由各种蛋白质和蛋白多糖组成 并将上皮与真皮分离。真皮是器官的最内层， 包含许多不同类型的细胞，但主要由成纤维细胞组成。这些 成纤维细胞分泌皮肤结构所必需的各种蛋白质。我们已经发现 通过DTA消融和免疫荧光，这些成纤维细胞似乎抑制干细胞 消融导致组织内干细胞的过度增殖活性。这 这种关系强调了成纤维细胞在维持皮肤稳态中的重要性， 干细胞增殖有可能对皮肤有害，因为它可以增加皮肤炎的风险。 致癌突变我们项目的目的是通过以下方式解决不同的机制： 皮肤会自行修复，不同细胞成分的作用 维持皮肤的稳态我们的父母补助金的目的是解决以下主要问题： ”“怎么会呢 正常 细胞行为是否在单细胞和组织尺度上得到适当的协调， 随着机体衰老而保持体内平衡。 要求补充资金，以支持Deandra Simpson 24个月， 追求科学目标，准备和申请医学 科学家培训计划。Deandra将接受培训并承担不同方面的责任 补充提案中描述的研究。如“研究”中所述， 经验计划”，Deandra将协助一个项目，重点是了解关系 目的1中成纤维细胞和上皮干细胞增殖之间的关系：研究的新方法 不同的现象，有助于皮肤稳态控制再生和目标2： 学习如何在基因上操纵我们的模型生物， 皮肤稳态的破坏。我们最近的研究似乎表明， 成纤维细胞的增殖增加上皮干细胞在体内。然而，我们仍然缺乏一个详细的 从分子水平理解这些变化的原因。不同的遗传学方法将 用于描述导致这些变化的机制以及成纤维细胞的总体影响。 维持皮肤的稳态

Project Summary The skin is a dynamic organ comprised of three main layers, the topmost layer being the epithelium followed by the basement membrane and the dermis. Stem cells within the skin are located within the basal layer which is the innermost layer of the epithelium. Beneath this layer resides the basement membrane which is comprised of various proteins as well as proteoglycans and separates the epithelium from the dermis. The dermis is the innermost layer of the organ and contains numerous different types of cells but is primarily comprised of fibroblasts. These fibroblasts secrete various proteins that are essential for skin structure. We have discovered through DTA ablation and immunofluorescence that these fibroblasts appear to inhibit stem cell proliferation as ablation resulted in hyperproliferative activity of stem cells within the tissue. This relationship highlights the importance of fibroblasts in maintaining skin homeostasis as excess stem cell proliferation has the potential to be detrimental to the skin as it can increase the risk of cancer-causing mutations. The aim of our project is addressing the different mechanisms by which the skin goes about repairing itself, and the effect of the different cellular components have in maintaining skin homeostasis. The aim of our parent grant addresses the major question of “how normal are cell behaviors are properly orchestrated on the single-cell and tissue-scale level during homeostasis as the organism ages. Supplemental funding is requested to support Deandra Simpson for 24 months of postbaccalaureate work to pursue a scientific goal and to prepare for and apply to Medical Scientist Training Programs. Deandra will train and take on responsibility for the different aspects of the research described in the supplemental proposal. As described in the “Research Experience Plan”, Deandra will assist on a project focused on understanding the relationship between fibroblasts and epithelial stem cell proliferation in Aim 1: new approaches to investigate different phenomena that contribute to skin homeostatic control during regeneration and Aim 2: learning how to genetically manipulate our model organism to measure how these changes lead to disruption in skin homeostasis. Our most recent work seemed to demonstrate that the ablation of fibroblasts increases epithelial stem cell proliferation in vivo. However, we still lack a detailed molecular level understanding of the causes of these changes. Different genetic approaches will be used to delineate the mechanism that led to these changes and the overall impact of fibroblasts in maintaining skin homeostasis.