Engineered Hydrogel Elucidates the Contribution of ECM Stiffness to Barrett's Esophagus Pathogenesis

工程水凝胶阐明了 ECM 硬度对巴雷特食管发病机制的影响

• 批准号: 10664561
• 负责人: Ricardo Cruz Acuña
• 金额: $ 15.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664561
• 关键词: 3-Dimensional; Adenocarcinoma; Adhesives; Advisory Committees; Affect; Barrett Epithelium; Barrett Esophagus; Biochemical; Biocompatible Materials; Biologic Characteristic; Biology; Biomechanics; Biomedical Engineering; Cells; Characteristics; Clinic; Cues; Data; Development Plans; Disease; Dysplasia; Engineering; Environment; Epigenetic Process; Epithelial Cells; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophagus; Event; Extracellular Matrix; Faculty; Fostering; Foundations; Funding; Gene Expression; Gene Expression Profile; General Population; Genes; Growth; High grade dysplasia; Human; Hyaluronic Acid; Hydrogels; In Vitro; Individual; Injury; Institution; Intestinal Metaplasia; MDM2 gene; Medical center; Mentored Research Scientist Development Award; Mentorship; Metaplasia; Modeling; Morphology; Mutation; Organoids; Pathogenesis; Pathway interactions; Patients; Peptides; Persons; Pharmaceutical Preparations; Population; Pre-Clinical Model; Prevention; Proliferating; Property; Research; Research Personnel; Research Proposals; Risk; Role; Signal Transduction; Squamous Epithelium; System; TP53 gene; Testing; Time; Tissues; Training; United States National Institutes of Health; Universities; Work; Xenograft procedure; base editing; career development; clinically significant; collaborative environment; defined contribution; density; effectiveness testing; genomic aberrations; human disease; human model; in vivo; in vivo evaluation; induced pluripotent stem cell; inhibitor; innovation; intestinal epithelium; novel; novel therapeutics; permissiveness; pre-doctoral; response; small molecule inhibitor; stem cell derived tissues; stem cell model; targeted treatment; tenure track; therapeutic target; translational medicine; translational therapeutics; treatment response

Project Summary Barrett’s esophagus (BE) is a disease in which the squamous epithelium of the esophagus is replaced by a columnar intestinal epithelium (termed metaplasia), and is believed to affect 3-4 million people in the US. BE patients have a 30-125-fold greater risk of developing esophageal adenocarcinoma (EAC) via intermediate low- grade and high-grade dysplastic states, when compared to the general population. The pathogenesis of BE involves epigenetic/genomic aberrations (e.g. TP53 mutations), and an interplay with microenvironmental cues. Recent studies have demonstrated that ECM stiffening is associated with metaplasia (or BE)-dysplasia- adenocarcinoma sequence, and my novel data reveal that increased ECM stiffness, a critical biomechanical property, is characteristic of BE pathogenesis. This underscores a compelling need to understand mechanisms that foster BE metaplasia and dysplasia in the context of ECM stiffness. Therefore, this proposal will integrate my unique predoctoral training in biomaterial engineering with my new proposed career development training in epithelial cell and organoid biology to utilize an engineered HA-based hydrogel to elucidate the contribution of ECM stiffness in BE pathogenesis, and to identify matrix-activated therapeutic targets. This bioengineering approach will be combined with TP53 mutation (in the epithelium of BE) to understand BE pathogenesis. The overarching hypothesis of my proposal is that ECM stiffness modulation can recapitulate a dysplastic BE state, revealing novel underlying mechanisms of the disease. I will pursue this hypothesis through the following interrelated Specific Aims: Aim 1 focuses on establish a hydrogel platform to study the pro-dysplastic contribution of matrix properties in patient-derived BE organoids. Aim 2 focuses on in vitro identification and in vivo evaluation of therapeutic targets in stiff matrix-exposed patient-derived BE organoids. Aim 3 focuses on utilizing an hiPSC-derived platform of BE to elucidate the cooperation between intrinsic and extrinsic factors contributing to BE pathogenesis. This work is innovative because it uses an advanced bioengineering approach to elucidate the functional roles of ECM stiffness in human BE pathogenesis. Successful completion of this proposal will be both scientifically and clinically significant by defining the contribution of biomechanics to BE and laying a foundation for novel therapies to disrupt matrix stiffness in BE. The research proposal, training/career development/mentorship plans, advisory committee, RCR training, protected time for research, and institutional support will provide the foundation for me to transition to an eventual independent NIH funded tenure-track faculty investigator, who blends principles of basic biology, bioengineering, and translational medicine.

项目摘要 巴雷特的食道（BE）是一种疾病，其中食管的鳞状上皮被A取代 柱状肠上皮（称为Metaplasia），据信在美国影响3-40万人。是 患者通过中间低 - 与普通人群相比，年级和高级发育不良状态。 BE的发病机理 涉及表观遗传/基因组畸变（例如TP53突变），以及与微环境提示的相互作用。 最近的研究表明，ECM僵硬与化生 - dysplasia-- 腺癌序列和我的新数据表明，ECM刚度增加，这是一种关键的生物力学 特性是发病机理的特征。这强调了理解机制的迫切需求 在ECM刚度的背景下，这种寄养是化生和发育不良的。因此，该建议将集成 我在新建议的职业发展培训中，在生物材料工程方面的独特培训 上皮细胞和器官生物学利用基于HA的水凝胶来阐明 ECM刚度是发病机理，并鉴定基质激活的治疗靶标。这种生物工程 方法将与TP53突变（在BE的上皮中）结合使用，以理解为发病机理。这 我的提议的总体假设是ECM刚度调节可以概括不塑性的状态， 揭示了该疾病的新型潜在机制。我将通过以下来追求这一假设 相互关联的特定目的：AIM 1专注于建立一个水凝胶平台来研究促塑塑料 基质特性在患者衍生的是器官的贡献。 AIM 2专注于体外识别和 暴露于刚性基质的患者衍生的治疗靶标的体内评估是类器官。 AIM 3专注于 使用HIPSC衍生的BE平台来阐明内在因素和外在因素之间的合作 有助于发病机理。这项工作具有创新性，因为它使用了先进的生物工程方法 为了阐明ECM刚度在人体发病机理中的功能作用。成功完成 通过定义生物力学的贡献是，提案将在科学和临床上具有重要意义 并为新疗法奠定了破坏BE中基质刚度的基础。研究建议， 培训/职业发展/指导计划，咨询委员会，RCR培训，保护研究时间， 机构支持将为我过渡到独立NIH资助的活动的基础 终身教师调查员，融合了基本生物学，生物工程和翻译原则 药品。