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Mechanisms underlying regulation of intestinal epithelial homeostasis in sepsis

脓毒症肠上皮稳态调节的机制

基本信息

批准号：
10757097
负责人：
Xiao-Di Tan
金额：
$ 61.67万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10757097
关键词：
Abbreviations Achievement Affect American Animal Model Attenuated Biological Assay Bone Morphogenetic Proteins Cell Proliferation Cell Separation Cells Cellular biology Columnar Cell Columnar Epithelium Data Deoxyuridine Development Epithelial Cell Proliferation Epithelial Cells Equilibrium Event Flow Cytometry Fluorescent in Situ Hybridization Functional disorder Genetic Engineering Goals Gut Mucosa H19 gene Homeostasis Human IFITM1 gene Immune System Diseases Immune system Impairment In Vitro Infection Inflammation Inflammatory Inhibition of Cell Proliferation Interferon Type II Interleukin-6 Intestinal Mucosa Intestines Knockout Mice Knowledge LGR5 gene Label Life Lymphoid Malnutrition Mediating Methods Molecular Molecular Biology Molecular Target Molecular and Cellular Biology Multiple Organ Failure Natural regeneration Operative Surgical Procedures Organ Organoids Pathogenesis Patient-Focused Outcomes Patients Physiological Play Process Proliferating Proteins RNA Binding Regulation Research Role Sepsis Signal Transduction Specimen TP53 gene Techniques Technology Testing Trauma Traumatic injury Untranslated RNA Up-Regulation Villus WNT Signaling Pathway Work base cecal ligation puncture clinically relevant cytokine cytokine release syndrome dysbiosis epithelium regeneration gastrointestinal epithelium gut homeostasis improved in vivo interleukin-22 intestinal crypt intestinal epithelium intestinal homeostasis microbiome monocyte mouse genetics mouse model multidisciplinary new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics polymicrobial sepsis preservation response restoration self-renewal septic septic patients severe burns stem cell proliferation stem cells systemic inflammatory response

项目摘要

Sepsis and severe surgical conditions cause profound decrease in epithelial cell proliferation in the intestinal crypts. This pathophysiological response disrupts intestinal epithelial homeostasis, which is thought to contribute to the pathogenesis of sepsis-induced immune dysfunction and multiple organ failure. Evidence shows that sepsis is associated with increased levels of interferon γ (IFNγ), a proinflammatory cytokine known to inhibit intestinal epithelial cell (IEC) proliferation in vitro. In preliminary studies, we found that IFNγ plays an important role in disruption of crypt IEC proliferation in sepsis. The proliferative cells in the intestinal crypts are composed of Lgr5-expressing crypt base columnar cells (Lgr5+-CBCs, a group of intestinal stem cells [ISCs]) and transit amplifying cells (TACs). However, the mechanism by which sepsis-activated IFNγ signal affects proliferation of these cells has not been rigorously studied. Furthermore, little is known about how to sustain proliferation of Lgr5+-CBCs and TACs to maintain homeostasis in sepsis. Recently, we found that sepsis is associated with de novo expression of a long noncoding RNA (lncRNA) molecule, H19, in Lgr5+-CBCs and TACs in the intestinal crypts. Remarkably, we discovered that H19 lncRNA plays a critical role in attenuating sepsis-induced reduction of crypt IEC proliferation and promoting intestinal epithelial regeneration. Mechanistically, H19 lncRNA binds to molecules that inhibit cell proliferation and attenuates their activity. Collectively, these data suggest that IFNγ signaling and H19 lncRNA play opposing roles in the regulation of Lgr5+-CBC and TAC proliferation in sepsis. In this project, we will test the hypothesis that sepsis-induced inflammation activates de novo expression of H19 lncRNA, which in turn antagonizes the deleterious effect of the IFNγ signal axis, thereby releasing inhibition of Lgr5+-CBC and TAC proliferation and rescuing homeostasis of the intestinal mucosa. To achieve this goal, we will execute three complementary aims: (1) We will examine whether and how septic inflammation dysregulates proliferation of Lgr5+-CBCs and TACs by focusing on the role of IFNγ signaling. We will precisely study the harmful effect of sepsis on proliferation of Lgr5+-CBCs and TACs in vivo utilizing a clinically relevant mouse model of polymicrobial sepsis, a novel method that combines 5-ethynyl-2'-deoxyuridine labeling with multi-probe fluorescence in situ hybridization assay, and flow cytometry and cell sorting technology. Furthermore, we will delineate how IFNγ signaling leads to inhibition of Lgr5+-CBC and TAC proliferation in sepsis. (2) We will investigate the molecular mechanisms by which de novo expressed H19 lncRNA antagonizes the inhibitory effect of sepsis on Lgr5+-CBC and TAC proliferation, taking a multidisciplinary in vivo and in vitro approach that incorporates cell biology, organoid culture, molecular biology, and mouse genetic engineering techniques. (3) We will study how septic inflammation induces de novo expression of H19 lncRNA in IECs. Successful achievement of these aims will fill gaps in knowledge about the regulation of intestinal epithelial renewal in sepsis and ultimately lead to development of new therapies.

脓毒症和严重的手术条件导致肠道上皮细胞增殖严重减少

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice.

DOI：
10.3390/cells10040728
发表时间：
2021-03-25
期刊：
Cells
影响因子：
6
作者：
Bu HF;Subramanian S;Geng H;Wang X;Liu F;Chou PM;Du C;De Plaen IG;Tan XD
通讯作者：
Tan XD

Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.

DOI：
10.1080/19490976.2023.2267180
发表时间：
2023-12
期刊：
Gut microbes
影响因子：
12.2
作者：
通讯作者：

SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells.

DOI：
10.3389/fimmu.2021.679482
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Geng H;Subramanian S;Wu L;Bu HF;Wang X;Du C;De Plaen IG;Tan XD
通讯作者：
Tan XD

Novel Role of Ghrelin Receptor in Gut Dysbiosis and Experimental Colitis in Aging.

DOI：
10.3390/ijms23042219
发表时间：
2022-02-17
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Noh JY;Wu CS;DeLuca JAA;Devaraj S;Jayaraman A;Alaniz RC;Tan XD;Allred CD;Sun Y
通讯作者：
Sun Y

Severe gut mucosal injury induces profound systemic inflammation and spleen-associated lymphoid organ response.