Molecular Mechanisms of Physiologic Beta Cell Growth in Juvenile Human Pancreas

描述（由申请人提供）：作为人类胰岛研究网络（HIRN）的一部分，本申请加入靶向和再生联盟，旨在了解和定义“少年”（< 10岁）人类β细胞的分子特征和增殖特性，以制定促进成人β细胞功能、增殖和再生的策略。虽然我们对啮齿动物β细胞增殖特性的理解取得了显著进展，但我们无法安全地刺激人类β细胞的增殖。这部分是由于人类和啮齿动物β细胞的差异，但主要的限制是缺乏生理上适当和安全的人类β细胞增殖的例子。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，因为我们的研究团队成员的发现和青少年人类胰腺标本和胰岛的可用性，其中有生理上适当的人类β细胞团块扩张。这一建议是基于最近的观察，胎儿人β细胞具有极低的增殖率，但在出生后的第一个十年内，稳健的人β细胞增殖导致人β细胞质量的显着扩大。我们团队的发现表明，青少年胰岛与成人胰岛有明显的差异，并对增殖刺激如血小板衍生生长因子（PDGF）和胰高血糖素样肽-1 （GLP-1）有反应。催乳素和人胎盘乳原不刺激人β细胞增殖，但我们小组最近的一项发现提示了如何克服这一限制。我们假设幼年β细胞对有丝分裂刺激（如PDGF、GLP-1和催乳素）有活跃的信号通路，但这些信号通路在成人β细胞中变得不活跃。我们假设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。为了应对这一RFA，我们已经组建了一个基础广泛、互补和跨学科的科学团队，他们在人类胰岛生物学、细胞增殖和人类胰岛细胞分选方面具有专业知识。

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.