Integrative mouse pathobiology: GI epithelial biology and genetics

综合小鼠病理学：胃肠道上皮生物学和遗传学

• 批准号: 8690996
• 负责人: Hiroshi Nakagawa
• 金额: $ 10.16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-03 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690996
• 关键词: Advisory Committees; Affect; Benign; Biology; Carcinoma in Situ; Cell Culture Techniques; Cell Fate Control; Cell Line; Cells; Characteristics; Complex; Coupled; Cues; Cyclin D1; Data; Development; Disease; Disease Progression; Dominant-Negative Mutation; Dysplasia; Epithelial; Epithelial Cells; Esophageal; Esophageal Diseases; Esophageal Squamous Cell Carcinoma; Esophagus; Future; Genetic; Genetically Engineered Mouse; Goals; Growth; Growth Factor Inhibition; Heterogeneity; Histocompatibility Testing; Homeostasis; Human; Human Papillomavirus; Image; Intervention; Keratin; Knockout Mice; Knowledge; Laboratories; Lead; Life; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mentors; Mesenchymal; Mission; Modeling; Molecular; Morphology; Mus; Mutation; NOTCH1 gene; Nature; Oncogene Proteins; Outcome; Pathogenesis; Pathway interactions; Prevention; Primary Neoplasm; Public Health; Regulation; Research; Resistance; Role; Shapes; Signal Transduction; Skin; Squamous Differentiation; Squamous cell carcinoma; Staging; Stem cells; System; Testing; Time; Tissues; Training; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Biology; Tumor Suppressor Proteins; base; cancer stem cell; carcinogenesis; epithelial to mesenchymal transition; experience; gain of function; human disease; imaging modality; in vivo; innovation; insight; keratinocyte; loss of function; molecular imaging; mouse model; neoplastic cell; notch protein; novel; novel strategies; prevent; research study; response; senescence; trait; transcription factor; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Little is known about the role of Notch signaling in esophageal squamous epithelial biology and diseases. In particular, there is a fundamental gap in understanding how Notch signaling contribute to normal esophageal epithelial squamous differentiation, carcinogenesis, and intratumoral cell heterogeneity, characterized by co- existing well-differentiated cell nests (i.e. keratin pearl) and disseminated, invasive poorly differentiated cells with mesenchymal traits found in esophageal squamous cell carcinoma (ESCC), one of the most deadly cancers. Continued existence of this gap represents an important problem because, until it is filled, mechanisms for Notch-mediated esophageal epithelial cell fate regulation will remain largely incomprehensible. The long-term goal is to better understand the molecular mechanisms by which tissue microenvironment influences malignant transformation of esophageal squamous epithelial cells. The objective in this proposal is to define the roles of Notch signaling in normal biology and tumor biology of the esophagus using innovative genetically engineered mouse models. The central hypothesis is that Notch induces squamous differentiation and senescence in a CSL-dependent manner. During tumor progression, microenvironmental cues activate a CSL-independent pathway to enrich migratory cancer stem cells (CSCs). This hypothesis has been formulated on the basis of preliminary data produced in the applicants' laboratories. The rationale for the proposed research is that, once it is known how Notch control cell fates, they can be manipulated pharmacologically, resulting in novel and innovative approaches in the prevention and treatment of ESCC. Guided by strong preliminary data, this hypothesis will be tested by pursuing three interrelated Specific Aims: (1) To elucidate how Notch activities contribute to the early stages of esophageal carcinogenesis in new mouse models; (2) To determine the roles of Notch for tumor progression in a conditional p120-catenin knockout mouse model; and (3) To delineate the roles of Notch in mouse CSCs in a novel orthotopic transplantation model where the tumor microenvironment is recapitulated. Genetic gain-of-function and loss-of-function experiments will be done in an inducible fashion in new mouse models. In vivo live imaging will be performed to assess the Notch-regulated CSC activities in vivo. The proposed research is significant, because it is expected to vertically advance and expand understanding of mechanisms by which esophageal epithelial homeostasis is regulated and in turn, deregulated in esophageal diseases, both benign and malignant, and potentially other squamous diseases in other tissue types, all through an appreciation of mouse pathobiology. Such knowledge will lead to development of innovative pharmacological strategies that will manipulate Notch signaling to alter esophageal cell fates and have the potential to advance in the therapy of ESCC and prevention of disease progression.

描述（由申请人提供）：关于Notch信号在食管鳞状上皮生物学和疾病中的作用知之甚少。特别是，在理解Notch信号传导如何促进正常食管上皮鳞状分化、癌变和肿瘤内细胞异质性方面存在根本性差距，其特征在于共存的分化良好的细胞巢。（即角蛋白珠）和在食管鳞状细胞癌（ESCC）中发现的具有间充质性状的播散性、侵袭性低分化细胞，最致命的癌症之一这一缺口的持续存在是一个重要的问题，因为在缺口被填补之前，Notch介导的食管上皮细胞命运调控机制仍将在很大程度上难以理解。长期目标是更好地了解组织微环境影响食管鳞状上皮细胞恶性转化的分子机制。本提案的目的是使用创新的基因工程小鼠模型来定义Notch信号传导在食管的正常生物学和肿瘤生物学中的作用。中心假设是Notch以CSL依赖性方式诱导鳞状分化和衰老。在肿瘤进展过程中，微环境信号激活了一条不依赖于CSL的途径，以富集迁移性癌症干细胞（CSC）。这一假设是根据申请人实验室的初步数据提出的。这项研究的基本原理是，一旦知道Notch如何控制细胞命运，就可以对它们进行操纵，从而产生预防和治疗ESCC的新颖和创新方法。在强有力的初步数据的指导下，这一假设将通过追求三个相互关联的具体目标来检验：（1）阐明Notch活性如何在新小鼠模型中促进食管癌发生的早期阶段;（2）确定Notch在条件性p120-catenin敲除小鼠模型中对肿瘤进展的作用;（3）在一种新的原位移植模型中，在肿瘤微环境重现的情况下，阐明Notch在小鼠CSCs中的作用。将在新的小鼠模型中以诱导方式进行遗传功能获得和功能丧失实验。将进行体内活体成像以评估Notch调节的CSC体内活性。拟议的研究是重要的，因为它有望纵向推进和扩大对食管上皮稳态调节机制的理解，反过来，在良性和恶性食管疾病中解除调节，以及其他组织类型中的潜在其他鳞状疾病，所有这些都是通过对小鼠病理生物学的认识。这些知识将导致开发创新的药理学策略，这些策略将操纵Notch信号传导以改变食管细胞的命运，并有可能在ESCC治疗和预防疾病进展方面取得进展。