Wnt/beta-catenin signaling in exocrine pancreas developoment and regeneration

外分泌胰腺发育和再生中的 Wnt/β-连环蛋白信号传导

• 批准号: 7352759
• 负责人: Lewis C Murtaugh
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7352759
• 关键词: Acinar Cell; Acinus organ component; Address; Adult; Affect; Beta Cell; Cataloging; Catalogs; Cell Differentiation process; Cells; Clinical Research; Development; Developmental Biology; Diabetes Mellitus; Disease; Duct (organ) structure; Ductal; Embryo; Embryonic Development; Endocrine; Enzymes; Epithelial Cells; Epithelium; Exhibits; Exocrine pancreas; Family member; Future; Gastrointestinal tract structure; Gene Deletion; Gland; Growth; Health; Homeostasis; Human; In Vitro; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans; Knock-out; Label; Left; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Mesenchymal; Mesenchyme; Metaplasia; Modeling; Molecular Genetics; Mus; Natural regeneration; Organ; Organogenesis; Pancreas; Pancreatic Diseases; Pancreatitis; Pathway interactions; Phenotype; Process; Proteins; Recovery; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; To specify; Undifferentiated; Work; acute pancreatitis; beta catenin; body system; cell growth; cell type; critical developmental period; human disease; in vivo; insight; interest; islet; mutant; nestin protein; novel; pancreatic tumorigenesis; postnatal; precursor cell; prevent; progenitor; programs; research study; response to injury; tumorigenesis

Although the pancreas is a relatively small organ, tucked away in a corner of the digestive tract, its diseases have a disproportionately large impact on human health. These diseases include type I diabetes, pancreatitis and pancreatic cancer, and affect both the endocrine and exocrine compartments of the gland. The endocrine pancreas includes insulin-producing beta cells, resident in the islets of Langerhans, while the exocrine pancreas comprises digestive enzyme-secreting acinar cells andthe ducts through which their secretions are channeled to the gut. The research program of our lab reflects a conviction that a better understanding of pancreas developmental biology will promote efforts to treat or cure these diseases. In particular, we are interested in the intercellular signals that regulate pancreas development, as these may offer attractive targets for therapeutic intervention in pancreatic disease. We have shown that beta-catenin, an intracellular mediator of canonical Wnt signaling, is required in vivo for the initial formation of pancreatic acinar cells, and that canonical Wnt signaling components are expressed and apparently active in the embryonic and regenerating pancreas. The central hypothesis of the research proposed here is that development of acinar cells requires active Wnt signaling through the canonical, beta-catenin-dependent pathway. Furthermore, we hypothesize that this requirement applies not only to embryonic acinar development, but also to regeneration of acinar cells following injury. We propose three Specific Aims, using a combination of explant culture and mouse molecular genetics, to test these hypotheses. (1) We will establish the function of canonical Wnt signaling per se, including components upstream and downstream of beta-catenin, in the developing mouse pancreas. (2) We will determine the effects of beta-catenin deletion on the cell fate of pancreatic progenitor and precursor cells at multiple stages of organogenesis. (3) We will characterize the role of Wnt/beta-catenin signaling in the maintenance and injury-induced regeneration of adult acinar cells. Wnt signaling is critical to development and cancer in other organ systems, and our studies will delineate its potential roles in pancreatic organogenesis and regeneration. Furthermore, our research will generate critical insight into the mechanisms underlying adult pancreatic regeneration, a controversial phenomenon relevant to both stem cell therapeutics and tumorigenesis.

尽管胰腺是一个相对较小的器官，藏在消化道的角落里，但其疾病 对人类健康的影响不成比例。这些疾病包括I型糖尿病， 胰腺炎和胰腺癌，并影响腺体的内分泌和外分泌室。 内分泌胰腺包括产生胰岛素的β细胞，居住在Langerhans的胰岛中，而 外分泌胰腺包括消化酶分泌的腺泡细胞和管道。 分泌物被引导到肠道。我们实验室的研究计划反映了一个信念，即更好 了解胰腺发育生物学将促进治疗或治愈这些疾病的努力。在 特别是，我们对调节胰腺发育的细胞间信号感兴趣，因为 为胰腺疾病的治疗干预提供了有吸引力的靶标。我们已经证明了β-catenin， 胰腺初始形成需要体内的典型Wnt信号传导的细胞内介体 腺泡细胞，以及规范的Wnt信号传导组件表达并显然是活跃的 胚胎和再生胰腺。这里提出的研究的核心假设是 腺泡细胞的开发需要通过规范的β-catenin依赖性的主动Wnt信号传导 路径。此外，我们假设这一要求不仅适用于胚胎腺泡 发育，但也要在损伤后再生腺泡细胞的再生。我们提出了三个特定目标，使用 外植体培养物和小鼠分子遗传学的结合，以检验这些假设。 （1）我们会的 建立规范Wnt信号的功能本身，包括上游和下游的组件 β-catenin，在发育中的小鼠胰腺中。 （2）我们将确定β-catenin删除的影响 在器官发生的多个阶段，在胰腺祖细胞和前体细胞的细胞命运上。 （3）我们会的 表征Wnt/beta-catenin信号传导在维持和受伤诱导的再生中的作用 成人腺泡细胞。 Wnt信号对于其他器官系统中的发育和癌症至关重要，我们的 研究将描述其在胰腺器官发生和再生中的潜在作用。此外，我们的 研究将对成人胰腺再生的机制产生批判性见解， 有争议的现象与干细胞疗法和肿瘤发生有关。