Sex steroid signaling and adaptive growth of the intestine

性类固醇信号传导和肠道的适应性生长

基本信息

批准号：
10211623
负责人：
Bruce Alexander Edgar
金额：
$ 47.81万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-25 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211623
关键词：
Address Affect Arthropods Atlases Binding Sites Biological Assay Breast Cell Proliferation Cells Chronic Colorectal Cancer Data Degenerative Disorder Diabetes Mellitus Diagnosis Disease Drosophila genus Dysplasia Ecdysone Enterocytes Environment Epidermal Growth Factor Receptor Epithelial Cell Proliferation Epithelial Cells Estradiol Fat Body Female Fertility Fertilization Future Gastrointestinal tract structure Gatekeeping Gene Expression Gene Targeting Genes Genetic Gonadal Steroid Hormones Growth Health Hormones Human Hyperactivity Incidence Inflammation Inflammatory Intestines Knowledge Lead Learning Longevity Malignant Neoplasms Mammals Maps Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Methods Midgut Mitogens Mitotic Modeling Morphology Mus Nutrient Nutritional Obesity Organ Organoids Ovary Partner in relationship Physiological Physiology Play Predisposition Progesterone Prostate RNA Interference Reproduction Risk Role Route Sex Bias Signal Transduction Sports Steroid Receptors Steroids Testing Testis Testosterone Uterus Work base cell behavior cell growth cell type conditional knockout ecdysone receptor experimental study fitness fly human disease human stem cells in vivo insight intestinal epithelium intestinal homeostasis malignant stomach neoplasm novel nutrition organ growth overexpression progenitor receptor reproductive reproductive fitness reproductive organ sex sexual dimorphism single-cell RNA sequencing stem cell growth stem cell proliferation stem cell self renewal stem cells steroid hormone transcriptome sequencing tumorigenesis uptake

项目摘要

PROJECT SUMMARY Sex-specific steroid hormones control cell growth and proliferation in reproductive organs including the ovaries, breast, uterus, prostate and testes. But how they impact non-reproductive organs is less well known. Considering the sex-biased incidence of many common diseases (e.g. colorectal and gastric cancer), the physiological effects of steroid signaling on the non-sex organs probably have profound health-relevance. We discovered that the Drosophila steroid hormone, 20-hydroxy-ecdysone (20HE), promotes intestinal stem cell (ISC) proliferation and adaptive organ growth, causing the female fly’s intestine to nearly double in size after mating (4). 20HE is produced by the activated ovaries after mating, and stimulates ISC proliferation via its receptor EcR/Usp and downstream targets Broad and Eip75B. 20HE also triggers EGFR/ERK signaling via unknown mechanisms, and this is essential for ISC activation. Our data suggest that 20HE-dependent gut remodeling in females enhances nutrient uptake, fecundity and reproductive fitness. However, the 20HE-dependent hyperactivity of ISCs also increases the female predisposition to gut dysplasia and tumorigenesis, a fitness trade off that can shorten lifespan. Our findings raise many questions about how 20HE signaling re-configures the female gut, how this alters gut and whole-body physiology, and whether sex steroids play similar roles in mammals. Here we address these questions in four Specific Aims. First, we use cell type-targeted genetics to determine the functions of EcR signaling in ISCs and committed progenitors called enteroblasts (EB), focusing on how 20HE gene targets activate ISC growth, metabolism and division, and on how 20HE amplifies the stem cell pool. In Aim 2, we use single cell RNA sequencing to map the effects of 20HE on each of the five main gut cell types in vivo. We also perform in vivo EcR binding site analysis by CUT&Tag, to map direct 20HE:EcR gene targets in midgut progenitor cells. The combined data from these assays will give a comprehensive atlas of the gene expression network effects of 20HE signaling in the gut. In Aim 3 we test the hypothesis that 20HE optimizes nutrient delivery to the fly’s other organs (e.g. ovaries, fat body) by altering the growth, metabolism and/or digestive capabilities of gut enterocytes. In Aim 4, we conduct experiments in mouse intestinal organoids and mice, testing whether the human sex steroids estradiol, progesterone, and/or testosterone promote intestinal epithelial cell (IEC) proliferation and gut growth in mammals. These studies will provide insights into the action of sex steroids as mitogens, regulators of stem cell self-renewal, and mediators of metabolism and nutrient uptake. This work will provide paradigms and lead data for understanding the basis of the sex-biased incidence of many human diseases, notably those involving altered stem cell behavior such as cancer, chronic inflammation, degenerative, and metabolic diseases.

项目概要性别特异性类固醇激素控制生殖器官（包括卵巢）的细胞生长和增殖，但它们如何影响非生殖器官却鲜为人知。许多常见疾病（例如结直肠癌和胃癌）的性别偏向发病率、生理效应我们发现非性器官上的类固醇信号传导可能与健康具有深远的相关性。果蝇类固醇激素 20-羟基蜕皮激素 (20HE) 可促进肠干细胞 (ISC) 增殖和适应性器官生长，导致雌性果蝇交配后肠道大小几乎翻倍 (4)。交配后由激活的卵巢产生，并通过其受体 EcR/Usp 刺激 ISC 增殖下游目标 Broad 和 Eip75B 也通过未知机制触发 EGFR/ERK 信号传导，并且这对于 ISC 激活至关重要。我们的数据表明，女性体内 20HE 依赖性肠道重塑会增强。然而，ISC 的 20HE 依赖性过度活跃也会影响营养吸收、繁殖力和生殖适应性。增加女性肠道发育不良和肿瘤发生的倾向，这是一种可以缩短肠道发育不良和肿瘤发生的健康权衡我们的研究结果提出了许多关于 20HE 信号如何重新配置女性肠道的问题。改变肠道和全身生理机能，以及性类固醇是否在哺乳动物中发挥类似的作用。这些问题有四个具体目标：首先，我们使用细胞类型靶向遗传学来确定 EcR 的功能。 ISC 和称为肠母细胞 (EB) 的定型祖细胞中的信号传导，重点关注 20HE 基因如何靶向激活 ISC 生长、代谢和分裂，以及 20HE 如何放大干细胞库。在目标 2 中，我们使用了 20HE。我们还通过单细胞 RNA 测序绘制了 20HE 对体内五种主要肠道细胞类型的影响。通过 CUT&Tag 进行体内 EcR 结合位点分析，以绘制中肠祖细胞中的直接 20HE:EcR 基因靶标这些测定的综合数据将给出基因表达网络的综合图谱。在目标 3 中，我们测试了 20HE 优化营养物质输送到肠道的假设。通过改变肠道的生长、代谢和/或消化能力来影响果蝇的其他器官（例如卵巢、脂肪体）在目标 4 中，我们在小鼠肠道类器官和小鼠中进行了实验，测试是否人类性类固醇雌二醇、黄体酮和/或睾酮促进肠上皮细胞 (IEC) 这些研究将深入了解性类固醇的作用。这项工作将促进有丝分裂原、干细胞自我更新的调节剂以及代谢和营养吸收的调节剂。提供范式和主要数据，以了解许多人类性别偏见发生率的基础疾病，特别是那些涉及干细胞行为的疾病，如癌症、慢性炎症、退行性疾病、和代谢性疾病。