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

虽然胰腺是一个相对较小的器官，藏在消化道的角落里，但它的疾病 对人类健康有着不成比例的巨大影响。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区室。 内分泌胰腺包括产生胰岛素的β细胞，驻留在胰岛中， 外分泌胰腺包括分泌消化酶的腺泡细胞和导管， 分泌物被引导到肠道。我们实验室的研究计划反映了一种信念， 对胰腺发育生物学的理解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，因为这些信号可能 为胰腺疾病的治疗干预提供了有吸引力的靶点。我们已经证明β-连环蛋白， 一种典型Wnt信号传导的细胞内介质，在体内是胰腺癌的初始形成所需的。 腺泡细胞，并且典型的Wnt信号传导组分在腺泡细胞中表达并明显活跃。 胚胎和再生胰腺。本研究的中心假设是， 腺泡细胞的发育需要通过典型的、β-连环蛋白依赖的Wnt信号传导。 通路此外，我们假设这一要求不仅适用于胚胎腺泡， 发育，而且损伤后腺泡细胞的再生。我们提出了三个具体目标，使用 外植体培养和小鼠分子遗传学的组合，以测试这些假设。(1)我们将 建立规范Wnt信号传导本身的功能，包括Wnt信号传导上游和下游的组件。 β-连环蛋白，在发育中的小鼠胰腺中。(2)我们将确定β-连环蛋白缺失的影响 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。(3)我们将 表征Wnt/β-连环蛋白信号传导在维持和损伤诱导的再生中的作用， 成年腺泡细胞Wnt信号传导对其他器官系统的发育和癌症至关重要， 研究将阐明其在胰腺器官发生和再生中的潜在作用。而且我们的 这项研究将对成人胰腺再生的机制产生重要的见解， 这是一个与干细胞治疗和肿瘤发生相关的有争议的现象。

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.