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性免疫性疾病， 表皮的过度增生。干细胞（SC）的分裂行为在恶性胶质瘤过度增殖中的作用 银屑病以前没有被提及。 初步数据：作为我们上次完成的Merit审查的一部分，我们提供的证据表明， 致癌性过度增殖与对称SC分裂（产生增加数量的SC）有关， 良性过度增殖与增加的不对称SC分裂有关（SC数量无变化）。在 在之前Merit的后续研究中，我们发现银屑病中不对称SC分裂的增加 具有白细胞介素17 A依赖性（Charruyer et al，2017）。 假设：在目标1中，我们假设观察到的SC分裂的增加是由于 活跃地循环SC，而不是细胞周期持续时间的变化，并且祖细胞转运的增加 基底上层中的放大细胞（TAC）是SC行为变化的下游结果 而不是增加战术小组的“回合”。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17 A的SC与载体处理的角质形成细胞的SC。 短期目标：在目标1中，我们将完成研究，以充分阐明如何改变SC和TAC动力学 导致银屑病的棘层（增厚）表皮。在目标2中，我们将确定基因的变化， 改变SC行为的潜在途径;与静止和不对称SC相关的途径 分裂，使用RNAseq，然后验证这些基因/途径与银屑病和角质形成细胞相关 使用正常和银屑病人角质形成细胞的SC自我更新。 长期目标：目标1的研究旨在实现相关的新数学模型， 牛皮癣作为未来的目标。目标2将阐明目标1改变的分子机制， 为供应链部门行为的操纵提供策略。沿着更好的理解 这些研究将使我们更接近重要的治疗目标：靶向 逃避常规治疗的静止/休眠癌细胞，以减少SC静止/增加 对称SC分裂，以帮助伤口愈合，并恢复不对称SC分裂之间的平衡 和对称SC分裂在银屑病和其它过度增殖性疾病的治疗中的应用。