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

定义突变负担在衰老过程中维持正常稳态的作用

• 批准号: 10554682
• 负责人: Valentina Greco
• 金额: $ 8.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554682
• 关键词: Ablation; Address; Age; Aging; Animal Model; Basement membrane; Biological; Cells; Dermis; Epithelial; Fibroblasts; Funding; Goals; Homeostasis; Immunofluorescence Immunologic; Lead; Learning; Link; Malignant Neoplasms; Measures; Medical; Molecular; Mutation; Natural regeneration; Normal Cell; Organ; Organism; Proteins; Proteoglycan; Research; Role; Scientist; Skin; Stratum Basale; Structure; Tissues; Training; Training Programs; Work; cancer risk; cell behavior; cell type; epithelial stem cell; experience; genetic approach; genetic manipulation; healthy aging; in vivo; innovation; insight; novel strategies; parent grant; repaired; stem cell proliferation; stem cells

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.

项目概要 皮肤是一个动态器官，由三个主要层组成，最顶层是 上皮细胞接着是基底膜和真皮。皮肤内的干细胞是 位于基底层内，基底层是上皮的最内层。在这一层之下 存在由各种蛋白质和蛋白聚糖组成的基底膜 并将上皮与真皮分开。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 成纤维细胞分泌对皮肤结构至关重要的各种蛋白质。我们发现 通过 DTA 消融和免疫荧光表明这些成纤维细胞似乎抑制干细胞 消融增殖导致组织内干细胞的过度增殖活性。这 这种关系凸显了成纤维细胞在维持皮肤稳态方面的重要性 干细胞增殖可能对皮肤有害，因为它会增加以下风险： 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作用 维持皮肤稳态。我们的家长补助金的目的是解决以下主要问题： “如何 普通的 细胞行为是否在单细胞和组织尺度水平上得到了适当的协调 随着有机体年龄的增长而保持体内平衡。 请求补充资金支持 Deandra Simpson 24 个月 学士学位后的工作是为了追求科学目标并为医学专业做准备和申请 科学家培训计划。 Deandra将负责不同方面的培训和责任 补充提案中描述的研究。正如《研究 体验计划”，Deandra 将协助一个专注于了解关系的项目 目标 1 中成纤维细胞和上皮干细胞增殖之间的关系：研究新方法 在再生和目标 2 过程中有助于皮肤稳态控制的不同现象： 学习如何基因操纵我们的模型生物来测量这些变化如何导致 破坏皮肤稳态。我们最近的工作似乎表明消融 成纤维细胞的增加可增加体内上皮干细胞的增殖。但我们还缺乏详细的 分子水平上了解这些变化的原因。不同的遗传方法将 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 维持皮肤稳态。