Effects of inflammaging on intestinal epithelial cells and aspirin chemoprevention.

炎症对肠上皮细胞的影响和阿司匹林化学预防。

• 批准号: 10383683
• 负责人: Andrew T Chan
• 金额: $ 60.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383683
• 关键词: APC gene; Address; Adult; Advisory Committees; Age; Aging; Aspirin; Benefits and Risks; Biological; Biological Assay; Biological Markers; Biopsy; Cancer Model; Cell Count; Cell Culture Techniques; Cell physiology; Cells; Chemoprevention; Chemopreventive Agent; Chemoprotective Agent; Chronic Disease; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Depreciation; Development; Dinoprostone; Dose; Double-Blind Method; Elderly; Enrollment; Epithelial; Epithelial Cells; Etiology; Experimental Models; Gene Expression Profile; Genetic; Guidelines; Human; Incidence; Individual; Inflammaging; Inflammatory; Intervention; Intestinal Cancer; Intestines; LGR5 gene; Lead; Life; Measures; Mediating; Methods; Modeling; Mucous Membrane; Mus; Mutation; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Organoids; Pathway interactions; Patients; Pharmacology; Placebo Control; Population; Pre-Clinical Model; Preventive service; Process; Prostaglandin Inhibition; Prostaglandins; Randomized Controlled Trials; Reporter; Reporting; Resistance; Resolution; Role; Secondary to; Shapes; Signal Transduction; Small Intestines; Testing; age effect; age related; aged; anti-cancer; biomarker development; cancer biomarkers; colorectal cancer prevention; colorectal cancer risk; disorder prevention; epithelial stem cell; fetal; human old age (65+); in vitro Model; in vivo; intestinal epithelium; mortality; mouse model; novel; pre-clinical; premalignant; receptor; regenerative; single-cell RNA sequencing; stem cell function; stem cells; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic; urinary; young adult

PROJECT ABSTRACT Previous randomized controlled trials (RCT)s demonstrate that low-dose aspirin (LDA, 81-100mg/day) reduces the risk of colorectal cancer (CRC). The U.S. Preventive Services Task Force (USPSTF) recommends LDA to prevent CRC in adults aged 50-59. However, a recent RCT among 19,114 older (65+) individuals reported that initiating LDA late in life had no benefit on CRC incidence and was potentially detrimental for mortality. Because CRC incidence rises with age, understanding the relationship and functional impact of aging on the chemopreventive effects of LDA is a high priority. Our working model is that the effect of LDA on the colon differs in older individuals due to age-related changes in intestinal stem cell (ISC) number and function secondary to a process of higher basal inflammatory tone, a.k.a. “inflammaging”. Normally, CRC appears to be primarily driven by oncogenic mutations in Lgr5+ ISCs and aspirin-like NSAIDs appear to preferentially eliminate premalignant Lgr5+ ISCs. However, our preliminary data demonstrates that old mice (20-22 months [mos]), as compared to young mice (2-3 mos), have fewer, less regenerative small intestinal Lgr5+ ISCs, which are also less tumorigenic in an Apc tumor suppressor model. Nonetheless, like humans, aged mice spontaneously develop a greater number of tumors, indicating that non-Lgr5+ cells are also the origin of intestinal cancers in aged mice and that these cells are less sensitive to LDA. LDA modulates prostaglandin (PG) levels, including PGE2. We also find that PGE2 impacts ISC function through its receptor Ptger4 and this signaling can drive ISCs into a fetal-like state (Hopx+) that is mediated by Hippo/Yap signaling. Thus, in the setting of inflammaging, elevated PGE2 may irreversibly compromise the colon (cISC) pool leading to compensatory functions within select cISCs that promote tumorigenesis. Through our double-blind, placebo-controlled RCT, we demonstrated that modulation of PG tone and inhibition of PG synthesis is central to aspirin’s mode of action. Our central hypothesis is that aging and age-related processes promote a decrease in the cISC pool (Lgr5+ cISCs) that is normally sensitive to aspirin chemoprevention. We propose that initiation of LDA earlier in life protects against this age-related, inflammation-associated, and/or PGE2-mediated damage to the cISC pool. In contrast, with advancing age there may be a “point-of-no-return” in which initiation of LDA is no longer protective against age- related changes in the cISC pool. In this proposal, we will expand our existing RCT to examine the impact of LDA on colonic epithelium at single cell resolution, patient-derived organoids, and urinary PGs in older adults. We will use novel in vivo preclinical models to dissect the role of inflammaging on PG signaling and LDA on cISCs. We will then examine the causality of these pathways on colon tumor incidence and progression. These studies may offer a biological explanation for the unexpected finding of a differential effect of LDA in older adults, which may influence clinical guidelines or the development of biomarkers to optimize LDA’s risk-benefit profile.

项目摘要