Ryan M. Anderson, PhD Assistant Professor, Department of Pediatrics
Assistant Professor: Department of Pediatrics
Basic Science Joint Appointment: Department of Cellular & Integrative Physiology
Postdoctoral: University of California San Francisco, Department of Biochemistry and Biophysics. Mentor: Didier Stainier.
Graduate: Duke University, Ph.D. Cell & Developmental Biology, Advisor: John Klingensmith, Dissertation title: Cellular and molecular mechanisms of mammalian head formation.
Undergraduate: University of Illinois Urbana-Champaign, BS, Biochemistry, BS, Honors Biology.
Pub Med Search
Areas of Study:
Cellular and molecular mechanisms of vertebrate pancreas formation and regeneration, developmental genetics.
Current Research Interests:
Worldwide, diabetes mellitus is a major cause of premature death, and its incidence and prevalence are on the rise. Diabetes is a collection of disorders that results from the failure of insulin signaling to keep pace with metabolic demands. In both major types of diabetes, the mass of functional insulin-secreting beta cells is diminished: in type 1 this happens through autoimmune attack, while in type 2, insulin resistance leads to beta cell destruction by multiple mechanisms, including inflammation of the pancreatic islets (home to the beta cells), and beta cell exhaustion. The therapeutic restoration of beta cell mass would cure or ameliorate both types of diabetes. One approach to restoration is the transplantation of exogenous islets. Even though this therapy has demonstrated promise, it is limited by the scarcity of donor islets. However, we believe that if the steps of beta cell generation during embryonic development were more thoroughly understood, then these steps could be recapitulated in vitro, in pluripotent stem cells. This could produce a vast new source of beta cells for transplant. A second approach to beta cell restoration is the stimulation of endogenous repair mechanisms. Although mammals have a limited capacity for islet regeneration, they may retain developmental and/or ancestral pathways that are typically dormant in adults. By studying the recovery from beta cell loss in other vertebrates with homologous pancreas structure, we can uncover key repair pathways. These can be then be unlocked genetically or pharmacologically to enhance adult beta cell regeneration.
To further these ends, we are using Danio rerio, a tropical fish commonly known as the zebrafish, to explore the developmental origins of pancreatic beta cells and the molecular pathways that govern their differentiation. Importantly, the composition and architecture of the zebrafish pancreas are remarkably conserved with mammals, as is the genetic control of pancreatogenesis. However, as model organisms, zebrafish have many unique advantages over traditional mammalian models. For instance: a pair of zebrafish can produce hundreds of developmentally synchronized embryos weekly. These are externally fertilized and transparent, which when coupled with the use of fluorescent transgenes, greatly facilitates the study of pancreatic development in living animals. The large size of zebrafish zygotes facilitates both the production of transgenic lines and rapid genetic analysis via the injection of DNA constructs, mRNAs, and antisense morpholinos. We use these techniques hand in hand with a burgeoning array of genetic, genomic, and bioinformatic tools, such as extensive libraries of genomic and cDNA clones, vast genomic sequence data, and hundreds of available mutant and transgenic lines. We are bringing all of these advantages of zebrafish to bear in order to rapidly elucidate mechanisms of pancreatic development and repair.
Specifically, my lab is investigating the following areas:
- What are the critical genetic regulators of pancreas morphogenesis and cytodifferentiation? How do these genes/pathways drive cell behavior and fate in the contexts of pancreas development and beta cell regeneration?
- How do epigenetic mechanisms, like DNA methylation, steer cell differentiation during pancreatogenesis, and how do they stabilize cell fate in the mature pancreas? How plastic are mature pancreatic cell fates, and how can plasticity be manipulated for de novo beta cell production?
To find answers to these questions, we have built an extensive toolkit that includes: a transgenic zebrafish model of beta cell depletion that is both inducible and reversible, a set of genetic lineage tracing tools based on cre-lox system to follow cell fates during development and regeneration, fluorescent transgenic lines which illuminate specific cell types in the developing and mature pancreas, and several characterized and uncharacterized pancreas mutants that exhibit defects in pancreas formation and cytodifferentiation.