Richard Glynne, Ph.D.
Director of Genetics
The aim of basic research within the Organismal Department is twofold—to gain an understanding of a poorly understood cellular organelle called the primary cilium and to apply genomics and chemical tools to manipulate the innate immune system, particularly mast cell activation.
The Primary Cilium
The primary cilium plays distinct roles in diverse pathologies, and almost all mammalian cells have a primary cilium and associated basal body. The function of this primitive cellular organelle has been poorly understood, both from a physiological and molecular standpoint. Recently, however, a causative role for mutations in proteins that localize to the cilium has been demonstrated in polycystic kidney disease, obesity, and sensory epithelia. Additionally, some evidence points to an exclusive relationship between cellular proliferation and cilium formation.
We are interested in identifying the mechanisms regulating formation of cilia and the role of cilia in sensory and metabolic physiology by using gene expression, mouse genetics, and cell biology. A comparative genomics study has identified a set of genes specifically conserved in ciliated organisms. This set of genes includes several that, when mutated, cause a spectrum of phenotypes in humans named Bardet Biedl Syndrome (BBS). BBS is typified by obesity, retinal degeneration, kidney malfunction, mental retardation, and dysmorphic extremities.
A similar, though not identical, spectrum of phenotypes is present in a rare recessive disease called Alstrom syndrome, believed to be caused by loss of function mutations in Alms1. Interestingly, the Alms1 protein is localized in the centrosome and might be a subunit of the cilium basal body. We are currently using cell and animal models to test the possibility that Alms1 protein is necessary for formation or function of primary cilia.
Immune System Research
Another area of study yielding to the combination of technology and science is basic research related to the immune system. Specifically, we are working to better understand the role of mast cells in immune disorders.
Genetic data and other evidence has long demonstrated that mast cells play a central role in several diseases, including asthma, multiple sclerosis, and rheumatoid arthritis, and there is reason to believe that manipulating these cells may be of some benefit to people who suffer from these conditions. In fact, existing drugs used to treat allergies and atopic diseases target the histamine and leukotriene pathways and act to inhibit the action of mast cell products. Additionally, a biological agent that blocks the IgE antibody, which activates mast cells through the IgE receptor, has efficacy in blocking mast cells activation.
However, small molecules that block mast cell activation directly are not in common clinical use. We are using small molecule inhibitors, proteomics, and pharmacological models to define the mechanism of action of a known regulatory pathway for mast cell survival and activation. Our end goal is to understand whether inhibition of this pathway might be a useful therapeutic strategy for treatment of asthma. Additionally, we plan to use genomics tools developed at GNF to identify new ways of manipulating mast cell function.
Selected Publications
