Novel mechanism of intestinal stem cell aging

肠道干细胞衰老的新机制

• 批准号: 10436391
• 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/10436391
• 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; Lead; Ligands; Link; Longevity; Measurable; Mesenchyme; Molecular; Mus; Muscle; Natural regeneration; Organ; Organoids; Paneth Cells; Phenotype; Physiological; Play; Process; Proliferating; Regenerative capacity; Role; 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.

摘要 许多具有高细胞周转率的哺乳动物器官（例如皮肤、肠和血液）由短寿命的 需要体干细胞持续补充的细胞。衰老导致这些组织 来维持体内平衡过去十年积累的证据表明， 从成年到老年，各种器官中的干细胞活性随年龄而下降，包括 造血、肠和肌肉。这种与年龄相关的干细胞功能的下降导致干细胞功能的下降。 人类和小鼠的再生能力，这可能会限制寿命。确定老年人 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 设计合理的方法来改善临床上的干细胞老化。根据初步结果，我们 假设β-连环蛋白信号的下降和相关的微生物群变化在以下方面起着因果作用： 在小鼠和人类中，ISC功能在衰老时发生变化。为了实现这一假设，我们将执行三个 目标。在目标1中，我们将通过以下方式确定单个ISCs中β-连环蛋白信号转导在衰老时的变化程度： 单细胞测序方法和Wnt表达变化对β-连环蛋白信号传导的影响， 衰老时ISC功能下降。在目标2中，我们将研究各种小生境细胞对 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 微生物群在小生境细胞中Wnt配体表达和调节β-连环蛋白信号传导中的作用 的ISCs老化。这项研究将揭示β-连环蛋白相关变化的新机制， 信号和微生物群与肠干细胞的生理老化过程和组织中的改变 体内平衡。该提案的发现可能会导致未来的治疗干预， 组织老化