Molecular Mechanisms of Physiologic Beta Cell Growth in Juvenile Human Pancreas

描述(由申请人提供)：本申请加入靶向和再生联盟作为人类胰岛研究网络(HIRN)的一部分，旨在了解和定义“幼年”(&lt；10岁)人类β细胞的分子特征和增殖特性，以开发促进成人人类β细胞功能、增殖和再生的策略。虽然我们对啮齿动物β细胞的增殖特性的了解已经取得了显著的进展，但我们还不能安全地刺激人类β细胞的增殖。这在一定程度上是由于人类和啮齿动物β细胞的差异，但一个主要的限制是缺乏生理上合适和安全的人类β细胞增殖实例。幸运的是，我们相信与人类β细胞增殖相关的挑战和限制现在可以解决，这既是由于我们研究团队成员的发现，也是因为有可用的幼年人胰腺标本和胰岛，在这些标本和胰岛中可以生理地适当地扩增人β细胞团。这一建议是基于最近的观察结果，即胎儿β细胞的增殖率极低，但在出生后的第一个十年内，强劲的人类β细胞增殖导致人类β细胞团显著扩张。我们团队的发现表明，幼年人的胰岛与成年人的胰岛有明显的不同，并对增殖刺激做出反应，如血小板衍生生长因子(PDGF)和胰升糖素样肽-1(GLP-1)。催乳素和人胎盘催乳素不会刺激人β细胞的增殖，但我们小组最近的一项发现提出了如何克服这一限制的建议。我们假设幼年β细胞对有丝分裂原刺激如血小板衍生生长因子、胰岛素样生长因子-1和催乳素具有活跃的信号通路，但在成人β细胞中这些信号通路变得不活跃。我们推测，了解这些与年龄相关的变化将为模拟成人β细胞的生长提供途径。作为对RFA的回应，我们组建了一支基础广泛、互补性和跨学科的科学团队，在人类胰岛生物学、细胞增殖和人类胰岛细胞分选方面拥有专业知识。 我们提出了三个目标：1)研究PDGF1、GLP-1和催乳素对幼年人β细胞体内增殖的影响。2)重建成人β细胞对血小板衍生生长因子和催乳素的体内外反应性。3)破译年龄依赖性人β细胞增殖的信号基础。此外，我们的团队将为Hirn带来丰富的收购和研究人类幼年胰腺和胰岛的经验，以及一套独特的人类胰腺组织，这将使以前不可能进行的研究成为可能。

DESCRIPTION (provided by applicant): This application to join the Consortium on Targeting And Regeneration as part of the Human Islet Research Network (HIRN) seeks to understand and define the molecular signatures and proliferative properties of "juvenile" (< 10 years of age) human β cells in order to develop strategies to promote adult human β cell function, proliferation, and regeneration. While there have been remarkable advances in our understanding of the proliferative properties of rodent β cells, we are unable to safely stimulate the proliferation human β cells. Partly this is due to differences in human and rodent β cells, but a major limitation has been the lack of physiologically appropriate and safe examples of human β cell proliferation. Fortunately, we believe the challenges and limitations related to human β cell proliferation can now be addressed due both to discoveries by our research team members and the availability of juvenile human pancreatic specimens and islets in which there is physiologically appropriate expansion of human β cell mass. This proposal is based on recent observations that fetal human β cells have an extremely low proliferation rate, but within the firs decade after birth, robust human β cell proliferation leads a marked expansion of human β cell mass. Discoveries by our team have shown that juvenile human islets have distinctive differences from adult human islets and respond to proliferative stimuli such as platelet-derived growth factor (PDGF) and glucagon-like peptide-1 (GLP-1). Prolactin and human placental lactogen do not stimulate human β cell proliferation, but a recent finding from our group suggests how to overcome this limitation. We hypothesize that juvenile β cells have active signaling pathways in response to mitogenic stimuli such as PDGF, GLP-1, and prolactin, but that these become inactive in adult human β cell. We postulate that understanding these age-related changes will provide pathways to simulate growth of adult human β cells. In response to this RFA, we have formed a broad- based, complimentary and interdisciplinary scientific team with expertise in human pancreatic islet biology, cell proliferation, and human islet cell sorting. We propose three aims: 1) Investigate in vivo proliferation of juvenile human β cells in response to PDGF, GLP-1, and Prolactin. 2) Reconstitute in vitro and in vivo responsiveness of adult human β cells to PDGF and Prolactin. 3) Decode the signaling basis for age-dependent human β cell proliferation. In addition, our team will bring to HIRN substantial experience with acquirin and studying human juvenile pancreas and islets and a set of unique human pancreatic tissues that will enable studies not previously possible.