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

描述(申请人提供)：虽然胰腺是一个相对较小的器官，藏在消化道的一角，但它的疾病对人类健康的影响不成比例地大。这些疾病包括I型糖尿病、胰腺炎和胰腺癌，影响内分泌腺和外分泌腺。内分泌胰腺包括分泌胰岛素的β细胞，驻留在朗格汉斯的胰岛上，而外分泌胰腺包括消化酶分泌腺泡细胞和导管，它们的分泌物通过这些导管被输送到肠道。我们实验室的研究计划反映了一种信念，即对胰腺发育生物学的更好理解将促进治疗或治愈这些疾病的努力。特别是，我们对调节胰腺发育的细胞间信号感兴趣，因为这些信号可能为胰腺疾病的治疗干预提供有吸引力的靶点。我们已经证明，典型的Wnt信号的细胞内介质β-catenin在体内是胰腺腺泡细胞初始形成所必需的，并且典型的Wnt信号成分在胚胎和再生胰腺中表达并明显活跃。这项研究的中心假设是，腺泡细胞的发育需要活跃的Wnt信号，通过规范的、β-连环蛋白依赖的途径。此外，我们假设这一要求不仅适用于胚胎腺泡发育，也适用于损伤后腺泡细胞的再生。我们提出了三个具体的目标，使用外植体培养和小鼠分子遗传学的组合来验证这些假设。(1)我们将建立规范的Wnt信号本身的功能，包括β-连环蛋白的上游和下游成分，在发育中的小鼠胰腺。(2)研究β-连环蛋白缺失对胰腺祖细胞和前体细胞在器官发生的多个阶段的细胞命运的影响。(3)我们将研究Wnt/β-catenin信号在成体腺泡细胞维持和损伤诱导再生中的作用。WNT信号在其他器官系统的发育和癌症中起关键作用，我们的研究将描绘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关键的洞察力，这是一个与干细胞疗法和肿瘤发生有关的有争议的现象。

DESCRIPTION (provided by applicant): 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 and the 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.