Creeping fat and Crohn's disease associated strictures

蠕动脂肪和克罗恩病相关的狭窄

• 批准号: 10641679
• 负责人: Florian Rieder
• 金额: $ 39.3万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641679
• 关键词: 3-Dimensional; Ablation; Actins; Acyl Coenzyme A; Adipocytes; Affect; Animal Model; Automobile Driving; Carnitine Palmitoyltransferase I; Cell Proliferation; Cells; Cholesterol Esters; Coenzyme A Ligases; Collagen; Complex; Crohn' s disease; Cytometry; Data; Deposition; Development; Disease; Diverticulitis; Effector Cell; Excision; Exhibits; Exposure to; Extracellular Matrix; Fatty acid glycerol esters; Feedback; Fibronectins; Fibrosis; Focal Adhesion Kinase 1; Fostering; Goals; Health Benefit; Human; Hyperplasia; Immune; Immunohistochemistry; Inflammatory; Integrin Signaling Pathway; Integrins; Intestinal Fibrosis; Intestinal Obstruction; Intestines; Link; Lipids; LoxP-flanked allele; Mediating; Mediator; Mesenchymal; Mesentery; Metabolism; Mitochondria; Molecular; Mouse Strains; Mus; Muscle; Muscle Cells; Muscle Mitochondria; Muscularis Mucosa; Myosin Light Chains; Nonesterified Fatty Acids; Obstruction; Operative Surgical Procedures; PTK2 gene; Pathogenesis; Pathway interactions; Patients; Penetration; Phospholipids; Preventive; Proliferating; Role; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Sodium Dextran Sulfate; Source; Sulfonic Acids; System; Testing; Therapeutic; Transgenic Mice; Triglycerides; Ulcerative Colitis; United States National Institutes of Health; Western Blotting; antifibrotic treatment; cytokine; fatty acid metabolism; gain of function; gut inflammation; in vivo; intestinal injury; loss of function; migration; mitochondrial metabolism; mouse model; muscle metabolism; nitrobenzene; novel; novel therapeutics; prevent; response; temporal measurement; uptake

ABSTRACT More than half of Crohn’s disease (CD) patients develop stricture induced intestinal obstruction and ultimately requiring surgery. A mechanistic understanding of intestinal stricture formation is mandatory to develop novel preventive and therapeutic approaches. Hyperplasia of the muscularis propria (MP) rather than extracellular matrix (ECM) deposition is a major contributor to intestinal wall thickening and hence gut luminal narrowing. In intestinal segments affected by CD, wrapping of mesenteric fat around the bowel is typically observed, called ‘creeping fat’. This is specific for CD and highly associated with the presence of MP hyperplasia and stricturing disease (with or without internal penetrating disease). There are essentially no mechanistic data linking creeping fat with intestinal stricture formation or explaining creeping fat formation. Preliminary results show that mesenteric fat derived lipids selectively induce remarkable proliferation of human intestinal MP muscle cells (HIMC) via long-chain free fatty acids (LC-FFAs) metabolism and uptake into mitochondria through the transporter carnitine palmitoyltransferase 1A (CPT-1A). ECM released by activated HIMC, predominantly fibronectin (FN), selectively promotes migration of primary human mesenteric adipocytes (Ad) and Pre-Ad. This resembles formation of creeping fat around intestinal segments. Hence, we propose the following hypothesis: stricture formation in CD is the result of a feedback loop where creeping fat non-immune cell-derived factors induce smooth muscle cell hyperplasia leading to increased secretion of ECM which promotes further creeping fat formation. This hypothesis will be tested by three specific aims: Specific Aim 1. Define the mechanisms of creeping fat-induced smooth muscle cell hyperplasia. We will identify creeping fat derived mediators and their cellular source responsible for HIMC proliferation, focusing on FFA signaling pathways, proliferation, mitochondrial function and modulation of the proliferation pathways. Specific Aim 2. Determine the role of HIMC-derived ECM molecules in integrin-mediated adipocyte migration. We will investigate mechanisms of HIMC-derived ECM leading to fat migration using a loss-of-function and gain-of-function approach with the goal to identify specific integrin signaling pathways. Specific Aim 3. Investigate the effect of mesenteric fat deletion and mitochondrial muscle metabolism on intestinal smooth muscle hyperplasia in vivo. We will induce experimental fibrosis in two transgenic mouse strains that 1) exhibit fat deletion that can be temporally controlled and 2) delete the mitochondrial transporter CPT-1 prior to and after induction of experimental intestinal fibrosis specifically in -SMA positive muscle cells. In addition, we present the first mouse model for creeping fat, developing after repeated intestinal injury. We will assess creeping fat formation and resolution by temporally controlled deletion of FN selectively in -SMA positive muscle cells. If successful, this proposal will challenge the paradigm of purely immune-driven ECM deposition driving stricture formation and provide novel mechanisms to prevent or treat stricture associated intestinal obstruction in CD patients.

抽象的 克罗恩病（CD）患者的一半以上会引起狭窄引起的肠道反对，最终 需要手术。必须对肠道狭窄形成的机械理解来发展新颖 预防和治疗方法。 Muscularis Prepra（MP）而不是细胞外的增生 矩阵（ECM）沉积是肠壁增厚的主要因素，因此肠道狭窄。在 通常观察到受CD影响的肠段，肠系膜脂肪在肠周围包裹，称为 '蠕动脂肪'。这是针对CD的特异性，高度与MP增生和狭窄相关 疾病（有或没有内部穿透性疾病）。本质上没有机械数据链接到蠕变 脂肪形成肠道狭窄或解释蠕动的脂肪形成。初步结果表明 肠系膜脂肪得出的脂质有选择地诱导人肠道MP肌肉细胞的显着增殖 （HIMC）通过长链游离脂肪酸（LC-FFAS）代谢，并通过该线粒体摄取 转运蛋白肉碱棕榈转移酶1A（CPT-1A）。 ECM由激活HIMC发行，主要是 纤连蛋白（FN），有选择地促进原代人肠系膜脂肪细胞（AD）和AD的迁移。这 类似于在肠段周围蠕动脂肪的形成。因此，我们提出以下假设： CD中的狭窄形成是反馈循环的结果，其中蠕动的脂肪非免疫细胞衍生 因素诱导平滑肌细胞增生，导致ECM的分泌增加，从而促进 进一步蠕动的脂肪形成。该假设将通过三个特定目的进行检验：特定目的1。定义 爬行脂肪引起的平滑肌细胞增生的机制。我们将确定得出的蠕动脂肪 介体及其细胞来源负责HIMC增殖，重点是FFA信号通路， 增殖，线粒体功能和增殖途径的调节。具体目标2。确定 HIMC衍生的ECM分子在整联蛋白介导的脂肪细胞迁移中的作用。我们将调查机制 HIMC衍生的ECM，通过使用功能丧失和功能障碍的方法导致脂肪迁移 确定特定整合素信号通路的目标。特定目标3。研究肠系膜脂肪的效果 缺失和线粒体肌肉代谢在体内肠平滑肌增生。我们将诱导 在两个转基因小鼠菌株中的实验性纤维化1）可以暂时控制的暴露脂肪缺失 2）在诱导实验性肠纤维化之前和之后删除线粒体转运蛋白CPT-1 -SMA阳性肌肉细胞。此外，我们提出了第一个用于蠕动脂肪的鼠标模型， 反复肠道损伤后发育。我们将通过临时评估脂肪形成和分辨率 在-SMA阳性肌肉细胞中选择性地缺失FN。如果成功，该提议将挑战 纯粹由免疫驱动的ECM沉积物驱动狭窄形成的范式并提供新颖 CD患者预防或治疗狭窄相关的肠道反对的机制。

项目成果

MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes.

• DOI: 10.1016/j.celrep.2023.112249
• 发表时间: 2023-03-28
• 期刊: Cell reports
• 影响因子: 8.8

Mild neoterminal ileal post-operative recurrence of Crohn's disease conveys higher risk for severe endoscopic disease progression than isolated anastomotic lesions.

• DOI: 10.1111/apt.16804
• 发表时间: 2022-05
• 期刊: ALIMENTARY PHARMACOLOGY & THERAPEUTICS
• 影响因子: 7.6
• 作者: Bachour, Salam P.;Shah, Ravi S.;Lyu, Ruishen;Rieder, Florian;Qazi, Taha;Lashner, Bret;Achkar, Jean Paul;Philpott, Jessica;Barnes, Edward L.;Axelrad, Jordan;Holubar, Stefan D.;Lightner, Amy L.;Regueiro, Miguel;Cohen, Benjamin L.;Click, Benjamin H.
• 通讯作者: Click, Benjamin H.

Efficacy of Endoscopic Dilation of Gastroduodenal Crohn's Disease Strictures: A Systematic Review and Meta-Analysis of Individual Patient Data.

• DOI: 10.1016/j.cgh.2018.11.048
• 发表时间: 2019-11
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Bettenworth D;Mücke MM;Lopez R;Singh A;Zhu W;Guo F;Matsui T;James TW;Herfarth H;Goetz M;Mao R;Kurada S;Hampe J;Matthes K;Karstensen JG;Valli PV;Duijvestein M;D'Haens G;Jairath V;Qiu TB;Ding NS;Rogler G;Rieder F
• 通讯作者: Rieder F

IL-36 in chronic inflammation and fibrosis - bridging the gap?

• DOI: 10.1172/jci144336
• 发表时间: 2021-01-19
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Elias, Michael;Zhao, Shuai;Rieder, Florian
• 通讯作者: Rieder, Florian

Assessment of Inflammatory Bowel Disease Training Among Gastroenterology Fellows.

胃肠病学研究员炎症性肠病培训的评估。

• DOI: 10.1093/ibd/izad030
• 发表时间: 2023
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Al-Bawardy,Badr;Malter,Lisa;Ehrlich,AdamC;Rieder,Florian;Gaidos,JillKJ;Proctor,Deborah;Windish,DonnaM
• 通讯作者: Windish,DonnaM