|
 Department of Developmental
Biology and Medicine (Oncology Division)
Howard Hughes Medical Institute
Beckman Center B300
Stanford University School of Medicine
279 Campus Drive
Stanford, CA 94305-5329
|
 Understanding organ development
and achieving functional restoration of diseased organs is a broad
goal motivating intensive effort in biomedical research. Many vital
organs derive from the endodermal and mesodermal germ layers to form
the gastrointestinal and respiratory tracts, yet little is known
about the molecular and cellular programs that coordinate steps culminating
in proper organ morphogenesis and axial position, cell differentiation,
proliferation and physiologic function. Replacement or regeneration
of pancreatic islets of Langerhans, endocrine organs that secrete
insulin and glucagon, has emerged as a paradigm for organ restoration
in recent years. Deficiency of insulin-producing islet ß-cells underlies
the pathogenesis of diabetes mellitus, a disease with devastating
autoimmune (type 1) and pandemic (type 2) forms. However, islet replacement
in diabetes is ultimately limited by our inadequate understanding
of mechanisms controlling islet formation and growth. Thus, islet
replacement is a specific challenge to the consensus that knowledge
about solid organ development and expansion can be used to restore
organ function in human diseases.
|
 To
meet this challenge, my group has pioneered new approaches to create,
expand, and regenerate islets. We discovered Drosophila endocrine
cells, including insulin-producing cells, that are functional orthologs
of mammalian islet cells, and generated novel genetic screens to
identify evolutionarily conserved programs that control the development,
expansion and reprogramming of islet cells. We identified new FACS-based
methods to purify specific classes of cells that generate the pancreas
and islets in mice and humans, including definitive endoderm and
native pancreatic progenitor cells, providing a powerful platform
to accelerate use of pancreatic and embryonic stem cells for islet
studies and replacement. We elucidated new molecular pathways that
control proliferation of ß-cells in physiological settings or islet
tumors. We envision that modulation of these pathways will be useful
for stimulating expansion of functional islets for diabetes, and
for treating neuroendocrine cancer. Below, we summarize our major
research efforts and describe how our unique approaches to islet
and pancreas biology should culminate in diagnostic and therapeutic
paradigms for human diseases. |
|
