The role of IL17A and keratinocyte stem cells in human psoriasis.

IL17A 和角质形成细胞干细胞在人类牛皮癣中的作用。

• 批准号: 10426045
• 负责人: RUBY GHADIALLY
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426045
• 关键词: Address; Adult; Alcohol consumption; Antibodies; Behavior; Benign; Biological Response Modifier Therapy; Bromodeoxyuridine; CD44 gene; Cell Count; Cell Cycle; Cell Cycle Kinetics; Cell division; Cells; Complications of Diabetes Mellitus; Development; Disease; Economic Burden; Epidermis; Equilibrium; Flow Cytometry; Future; Generations; Genes; Goals; Health; Healthcare Systems; Homeostasis; Human; Immune; Immune System Diseases; Immunofluorescence Immunologic; In Vitro; Inflammatory; Interleukin-17; Interleukins; Kinetics; Life Style; Molecular; Oncogenic; Organ Culture Techniques; Pathway interactions; Population; Post-Traumatic Stress Disorders; Preparation; Production; Propidium Diiodide; Proteins; Psoriasis; Recombinant Proteins; Reporting; Research; Risk; Role; Severities; Signal Pathway; Skin; Skin Cancer; Stains; Stress; TFRC gene; Therapeutic; Tobacco use; Transcript; Veterans; aldehyde dehydrogenases; cancer cell; cancer stem cell; care costs; cell behavior; conventional therapy; design; differential expression; improved; keratinocyte; live cell imaging; mathematical model; neutralizing antibody; novel; novel therapeutics; prevent; progenitor; skin ulcer; stem; stem cell division; stem cell self renewal; stem cells; targeted treatment; transcriptome sequencing; wound healing

BACKGROUND: Psoriasis is a benign inflammatory immunological disorder characterized by hyperproliferation of the epidermis. The role of stem cell (SC) divisional behavior in the hyperproliferation of psoriasis has not been addressed previously. PRELIMINARY DATA: As part of our last completed Merit Review we provided evidence to show that while oncogenic hyperproliferation is associated with symmetric SC divisions (producing increased numbers of SCs), benign hyperproliferation is associated with increased asymmetric SC divisions (no change in SC number). In studies subsequent to the previous Merit, we showed that the increase in asymmetric SC divisions in psoriasis was interleukin 17A dependent (Charruyer et al, 2017). HYPOTHESES: in Aim 1 we hypothesize that the observed increase in SC divisions is due to an increase in actively cycling SCs rather than a change in cell cycle duration, and that the increase in progenitor transit amplifying cells (TACs) in the suprabasal layer is a downstream consequence of the change in SC behavior rather than an increase in 'rounds' of TAC divisions. In Aim 2 we hypothesize that genes associated with signaling pathways related to SC quiescence and to asymmetric SC division will be differentially expressed in the SCs of interleukin 17A versus vehicle-treated keratinocytes. SHORT TERM GOALS: In Aim 1 we will complete studies to fully elucidate how altered SC and TAC kinetics result in the acanthotic (thickened) epidermis of psoriasis. In Aim 2 we will determine the changes in gene pathways underlying the altered SC behavior; pathways associated with quiescence and asymmetric SC division, using RNAseq and then validate these genes/pathways as relevant for psoriasis and for keratinocyte SC self-renewal using normal and psoriasis human keratinocytes. LONG TERM GOALS: The studies of Aim 1 are designed to enable a relevant new mathematical modeling of psoriasis as a future goal. Aim 2 will elucidate molecular mechanisms underlying the alterations in Aim 1 and provide strategies for manipulation of SC divisional behavior. Along with better understanding hyperproliferative diseases, these studies will move us closer to important therapeutic goals: to target quiescent/dormant cancer cells that escape conventional therapies, to decrease SC quiescence/ increase symmetric SC divisions to aid wound healing, and to restore homeostasis between the balance of asymmetric and symmetric SC divisions in the treatment of psoriasis and other hyperproliferative diseases.

背景：银屑病是一种良性炎症免疫性疾病，其特征为 表皮过度增殖。干细胞（SC）分裂行为在过度增殖中的作用 牛皮癣以前尚未得到解决。 初步数据：作为我们上次完成的绩效审查的一部分，我们提供了证据表明，虽然 致癌性过度增殖与对称 SC 分裂（产生 SC 数量增加）相关， 良性过度增殖与不对称 SC 分裂增加有关（SC 数量无变化）。在 继之前的研究之后，我们发现银屑病中不对称 SC 分裂的增加 依赖白细胞介素 17A（Charruyer 等，2017）。 假设：在目标 1 中，我们假设观察到的 SC 分裂增加是由于 活跃的 SC 循环而不是细胞周期持续时间的变化，并且祖细胞转运的增加 基底层上的扩增细胞 (TAC) 是 SC 行为变化的下游结果 而不是增加 TAC 划分的“轮数”。在目标 2 中，我们假设与 与 SC 静止和不对称 SC 分裂相关的信号通路将在 白细胞介素 17A 的 SC 与载体处理的角质形成细胞的比较。 短期目标：在目标 1 中，我们将完成研究以充分阐明 SC 和 TAC 动力学如何改变 导致牛皮癣表皮棘皮症（增厚）。在目标 2 中，我们将确定基因的变化 SC 行为改变背后的途径；与静止和不对称 SC 相关的途径 使用 RNAseq 进行分裂，然后验证这些基因/通路与牛皮癣和角质形成细胞的相关性 SC 使用正常和牛皮癣人类角质形成细胞进行自我更新。 长期目标：目标 1 的研究旨在建立相关的新数学模型 牛皮癣作为未来的目标。目标 2 将阐明目标 1 和目标改变背后的分子机制 提供操纵 SC 分裂行为的策略。随着更好的理解 过度增殖性疾病，这些研究将使我们更接近重要的治疗目标： 逃避常规疗法的静止/休眠癌细胞，以减少 SC 静止/增加 对称 SC 分裂有助于伤口愈合，并恢复不对称 SC 之间的平衡平衡 和对称 SC 分裂用于治疗牛皮癣和其他过度增殖性疾病。