Novel mechanism of intestinal stem cell aging

肠道干细胞衰老的新机制

• 批准号: 10646426
• 负责人: YI ZHENG
• 金额: $ 50.57万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646426
• 关键词: Adult; Affect; Age; Aging; Architecture; Attenuated; Biological Assay; Blood; Cell Aging; Cells; Clinic; Data; Deterioration; Endothelial Cells; Family; Future; Gene Expression; Hematopoietic; Homeostasis; Human; In Vitro; Intestines; Laboratories; Ligands; Link; Longevity; Measurable; Mesenchyme; Molecular; Mus; Muscle; Natural regeneration; Organ; Organoids; Paneth Cells; Phenotype; Physiological; Play; Process; Proliferating; Regenerative capacity; Role; Shapes; Signal Transduction; Skin; Therapeutic Intervention; Tissues; WNT Signaling Pathway; Wnt proteins; age related; aged; base; beta catenin; cell type; crypt cell; design; functional decline; gut microbiota; human old age (65+); in vivo; member; microbial; microbiota; novel; prevent; progenitor; response; single cell sequencing; single-cell RNA sequencing; stem cell aging; stem cell function; stem cells

Abstract Many mammalian organs with high cellular turnover (e.g. skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Aging results in the inability of these tissues to maintain homeostasis. Evidence accumulated over the past decade has found measurable and successive age-dependent decline in stem cell activity from adulthood to old age, in various organs, including hematopoietic, intestinal and muscle. This age-associated decline in stem cell function leads to a decline in the regenerative capacity in humans and mice, which may limit lifespan. Identifying mechanisms under which aged stem cells become phenotypically and functionally similar to young stem cells may be a first step towards designing rationale approaches to ameliorate stem cell aging in the clinics. Based on our preliminary results we hypothesize that the declining beta-catenin signaling and associated microbiota changes play a causal role in ISC functional changes upon aging in both mice and humans. To pursue this hypothesis, we will perform three aims. In aim 1, we will determine the extend of changes in beta-catenin signaling in single ISCs upon aging via single-cell sequencing approaches and the impact of Wnt expression changes on beta-catenin signaling and a decline in the function of ISCs upon aging. In aim 2, we will investigate the contribution of various niche cells to aging-associated changes in beta-catenin signaling in ISCs in vivo. In aim 3, we will determine the role of microbiota in Wnt ligand expression in the niche cells and in regulating beta-catenin signaling and the function of ISCs upon aging. The proposed studies will unveil a new mechanism of changes in associating beta-catenin signaling and microbiota with the physiologic aging process of intestinal stem cells and alterations in tissue homeostasis. The findings of the proposal may lead to future therapeutic interventions preventing or reversing tissue aging.

抽象的 许多具有高细胞更新率的哺乳动物器官（例如皮肤、肠和血液）由短寿命的细胞组成。 需要成体干细胞持续补充的细胞。衰老导致这些组织丧失能力 以维持体内平衡。过去十年积累的证据已经发现可衡量且连续的 从成年到老年，各种器官中的干细胞活性呈年龄依赖性下降，包括 造血、肠道和肌肉。这种与年龄相关的干细胞功能下降导致 人类和小鼠的再生能力可能会限制寿命。确定老龄化的机制 干细胞在表型和功能上变得与年轻干细胞相似可能是迈向这一目标的第一步 设计改善临床干细胞衰老的基本原理方法。根据我们的初步结果，我们 假设β-连环蛋白信号传导的减弱和相关微生物群的变化在 小鼠和人类的 ISC 功能随衰老而变化。为了追求这个假设，我们将执行三个 目标。在目标 1 中，我们将通过以下方法确定单个 ISC 老化时 β-连环蛋白信号传导变化的程度： 单细胞测序方法以及 Wnt 表达变化对 β-catenin 信号传导的影响以及 衰老时 ISC 的功能下降。在目标 2 中，我们将研究各种生态位细胞对 体内 ISC 中 β-连环蛋白信号的衰老相关变化。在目标 3 中，我们将确定以下角色： 微生物群在微环境细胞中 Wnt 配体表达以及调节 β-连环蛋白信号传导和功能中的作用 老化后的ISCs。拟议的研究将揭示β-连环蛋白关联变化的新机制 信号传导和微生物群与肠道干细胞的生理老化过程和组织变化 体内平衡。该提案的研究结果可能会导致未来的治疗干预措施预防或逆转 组织老化。