Molecular Mechanisms of Physiologic Beta Cell Growth in Juvenile Human Pancreas

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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.