Molecular Mechanisms of Physiologic Beta Cell Growth in Juvenile Human Pancreas

描述（由申请人提供）：本申请加入作为人类胰岛研究网络（HIRN）一部分的靶向和再生联盟，旨在了解和定义“幼年”（< 10岁）人β细胞的分子特征和增殖特性，以开发促进成人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已经有了显著的进展，但我们无法安全地刺激人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学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β细胞增殖相关的挑战和局限性现在可以得到解决，这是由于我们的研究团队成员的发现以及青少年人胰腺标本和胰岛的可用性，其中存在生理学上适当的人β细胞群扩增。该提议基于最近的观察结果，即胎儿人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细胞群的显著扩增。我们团队的发现表明，幼年人胰岛与成年人胰岛有显著差异，并对血小板衍生生长因子（PDGF）和胰高血糖素样肽-1（GLP-1）等增殖刺激有反应。催乳素和人胎盘催乳素不刺激人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细胞对促有丝分裂刺激（如PDGF、GLP-1和催乳素）具有活性信号通路，但这些信号通路在成年人β细胞中变得无活性。我们假设，了解这些与年龄相关的变化将提供模拟成人β细胞生长的途径。针对这一RFA，我们组建了一个基础广泛、互补和跨学科的科学团队，拥有人类胰岛生物学、细胞增殖和人类胰岛细胞分选方面的专业知识。 我们提出了三个目标：1）研究体内幼年人β细胞对PDGF、GLP-1和催乳素的反应。2)重建成人β细胞对PDGF和催乳素的体外和体内反应性。3)解码年龄依赖性人β细胞增殖的信号基础。此外，我们的团队还将为HIRN带来大量的获取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，这将使以前无法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.