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 超过一半的克罗恩病 (CD) 患者会出现狭窄引起的肠梗阻，最终 需要进行手术才能开发新的肠道狭窄形成机制。 预防和治疗方法是固有肌层（MP）增生，而不是细胞外增生。 基质（ECM）沉积是肠壁增厚和肠腔狭窄的主要原因。 受 CD 影响的肠段，通常会观察到肠系膜脂肪包裹肠道，称为 “蠕动脂肪”是 CD 所特有的，与 MP 增生和狭窄密切相关。 疾病（有或没有内部穿透性疾病）基本上没有与蠕变相关的机制数据。 脂肪与肠狭窄的形成或解释蠕动脂肪的形成。 肠系膜脂肪来源的脂质选择性诱导人肠 MP 肌细胞显着增殖 （HIMC）通过长链游离脂肪酸（LC-FFA）代谢并通过线粒体摄取 转运蛋白肉碱棕榈酰转移酶 1A (CPT-1A) 主要由激活的 HIMC 释放。 纤连蛋白 (FN)，选择性促进原代人肠系膜脂肪细胞 (Ad) 和 Pre-Ad 的迁移。 类似于肠段周围蠕动脂肪的形成，因此，我们提出以下假设： CD 狭窄的形成是反馈循环的结果，其中蠕变脂肪非免疫细胞衍生 因素诱导平滑肌细胞增生，导致 ECM 分泌增加，从而促进 该假设将通过三个具体目标进行检验： 具体目标 1. 定义 我们将确定蠕变脂肪引起的平滑肌细胞增生的机制。 负责 HIMC 增殖的介质及其细胞来源，重点关注 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 分子在整合素介导的脂肪细胞迁移中的作用我们将研究机制。 HIMC 衍生的 ECM 使用功能丧失和功能获得方法导致脂肪迁移 目标是确定特定的整合素信号通路。 具体目标 3. 研究肠系膜脂肪的影响。 我们将诱导体内肠道平滑肌发育的缺失和线粒体肌肉代谢。 两种转基因小鼠品系的实验性纤维化，1）表现出可以暂时控制的脂肪缺失 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 特别是在 α-SMA 阳性肌肉细胞中。此外，我们提出了第一个蠕变脂肪小鼠模型， 我们将通过暂时评估蠕变脂肪的形成和消退。 在 α-SMA 阳性肌肉细胞中选择性控制 FN 缺失 如果成功，这一提议将受到挑战。 纯免疫驱动的 ECM 沉积驱动狭窄形成的范例，并提供了新颖的 预防或治疗 CD 患者狭窄相关肠梗阻的机制。

项目成果

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

溃疡性结肠炎临床试验中组织病理学整合标准化的国际共识。

• 发表时间: 2021
• 影响因子: 29.4
• 作者: Ma, Christopher;Sedano, Rocio;Almradi, Ahmed;Vande Casteele, Niels;Parker, Claire E;Guizzetti, Leonardo;Schaeffer, David F;Riddell, Robert H;Pai, Reetesh K;Battat, Robert;Sands, Bruce E;Rosty, Christophe;Dubinsky, Marla C;Rieder, Florian;Har
• 通讯作者: Har

Development of antifibrotic therapy for stricturing Crohn's disease: lessons from randomized trials in other fibrotic diseases.

开发用于限制克罗恩病的抗纤维化疗法：其他纤维化疾病随机试验的经验教训。

• 发表时间: 2022-04-01
• 影响因子: 33.6
• 作者: Lin, Si;Mao, Ren;Qian, Chenchen;Bettenworth, Dominik;Wang, Jie;Li, Jiannan;Bruining, David H;Jairath, Vipul;Feagan, Brian G;Chen, Min;Stenosis Therapy and Antifibrotic Research (STAR) Consortium;Rieder, Florian
• 通讯作者: Rieder, Florian

Review article: the sphingosine 1 phosphate/sphingosine 1 phosphate receptor axis - a unique therapeutic target in inflammatory bowel disease.

评论文章：1 磷酸鞘氨醇/1 磷酸鞘氨醇受体轴 - 炎症性肠病的独特治疗靶点。

• 发表时间: 2022-02
• 影响因子: 7.6
• 作者: Wang, Jie;Goren, Idan;Yang, Bo;Lin, Sinan;Li, Jiannan;Elias, Michael;Fiocchi, Claudio;Rieder, Florian
• 通讯作者: Rieder, Florian

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

MFGE8 通过 CES 酶的 HNF4γ 依赖性转录，将膳食脂肪酸的吸收与肠上皮细胞脂质储存的分解代谢联系起来。

• 发表时间: 2023-03-28
• 影响因子: 8.8
• 作者: Datta, Ritwik;Gholampour, Mohammad A;Yang, Christopher D;Volk, Regan;Lin, Sinan;Podolsky, Michael J;Arnold, Thomas;Rieder, Florian;Zaro, Balyn W;Verzi, Michael;Lehner, Richard;Abumrad, Nada;Lizama, Carlos O;Atabai, Kamran
• 通讯作者: Atabai, Kamran

Sweet Syndrome Associated with Active Inflammatory Bowel Disease: A Case Series of a Rare Extra-intestinal Manifestation.

与活动性炎症性肠病相关的甜蜜综合征：罕见的肠外表现的病例系列。

• 发表时间: 2023-09
• 影响因子: 3.1
• 作者: Sleiman, Joseph;Patel, Mihir;Khan, Muhammad Zarrar;Falloon, Katherine;Cohen, Benjamin;Click, Benjamin;Khanna, Urmi;Fernandez, Anthony P;Rieder, Florian
• 通讯作者: Rieder, Florian