Novel mechanism of intestinal stem cell aging

肠道干细胞衰老的新机制

• 批准号: 10263330
• 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/10263330
• 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