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

项目摘要 皮肤是一个动态器官，由三个主要层组成，最顶层是 上皮，然后是基底膜和真皮。皮肤中的干细胞是 位于上皮最内层的基底层内。在这一层下面 基底膜由各种蛋白质和蛋白多糖组成。 并将上皮与真皮分开。真皮是器官的最内层， 含有许多不同类型的细胞，但主要由成纤维细胞组成。这些 成纤维细胞分泌各种对皮肤结构至关重要的蛋白质。我们发现 通过DTA消融和免疫荧光，这些成纤维细胞似乎抑制了干细胞 作为消融的增殖导致组织内干细胞的过度增殖活动。这 关系强调成纤维细胞在维持皮肤动态平衡方面的重要性 干细胞增殖有可能对皮肤有害，因为它会增加患上 致癌突变。我们项目的目标是通过以下方式解决不同的机制 皮肤进行自我修复，以及不同细胞成分的影响 来维持皮肤的动态平衡。我们父母资助的目的是解决以下主要问题： “怎样做？ 正常 细胞行为在单细胞和组织尺度上是否得到了适当的协调 随着生物体年龄的增长，动态平衡。 请求补充资金，以支持迪安德拉·辛普森24个月 毕业后追求科学目标，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 补充提案中所述的研究。如《研究》中所述 体验计划“，Deandra将协助一个以理解关系为重点的项目 AIM 1中成纤维细胞与上皮干细胞增殖之间的关系：新的研究方法 再生过程中有助于皮肤动态平衡控制的不同现象和目标2： 学习如何通过基因操作我们的模型生物体来测量这些变化是如何导致 皮肤动态平衡被破坏。我们最新的研究似乎证明了消融 在体内，成纤维细胞可促进上皮干细胞的增殖。然而，我们仍然缺乏一个详细的 在分子水平上理解这些变化的原因。不同的遗传方法将 用来描述导致这些变化的机制和成纤维细胞的整体影响 来维持皮肤的动态平衡。

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.