Research Projects
A common feature of developing tissues in both invertebrates
and vertebrates is the establishment of key groups of cells called
"organizers", that control the proliferation and fates of cells within
forming tissues. These centers
produce
extracellular signals (morphogens) that eminate from organizer cells,
forming a protein concentration gradient in developing tissues that is
essential in providing the instructive cues for cell fate and
patterning decisions. However the mechanisms by which signaling
molecules navigate this extracellular environment and reach their
intended target cell has eluded solution to date. During recent years
many studies have isolated and characterized specific classes of
morphogens, revealing the remarkable conservation of sequence homology
and function of these secreted protein families. In particular, these
include the Wingless/Wnt (wg/Wnt)), Transforming growth factor β
(tgf-β), and Hedgehog (Hh) superfamiles of secreted morphogens. Their
role as mitogens regulating cell proliferation, cell fate decisions and
tissue patterning has shown a consistent theme; a dose-dependent
response to these morphogen molecules. My lab is interested in understanding how these morphogens move and establish a gradient of response in developing tissues.
(1) Bioinformatics: Computational Modeling of the Hedgehog Signaling Pathway |
Hedgehog Signaling Pathway Database
Several projects are underway involving computational genomic,and proteomic analysis of the Hedgehog signaling pathway. These results are enabling us to characterize and model the pathway in over 100+ organisms. As a way to share some of this data we have begun to develop an on-line database for the Hedgehog signaling pathway. This database contains:
- all genes known to be involved in the Hh pathway in various organisms. This includes DNA and protein sequence data, domain structure motifs, molecular interaction data
- all known gene targets of the Hh pathway derived from microarray and RNAi experiments involving the Hh pathway.
- all known human diseases associated with the Hh pathway. This includes experimental data on therapeutic agents and their molecular targets.
- protocols, tissue cell lines, and reagents used by Hh pathway researchers.
- annotations contributed by Hh researchers
(2) Cytonemes
In previous experiments we described the presence and
distribution of actin based cellular projections (cytonemes) that allow
cells at a distance to connect to organizing centers in developing
tissues. Cytonemes might thus provide a conduit by which morphogens
could be received and/or released at a distance. We are in the process
of testing this model using a variety of biochemical, molecular and genetic methods.
A) Genetic and biochemical analysis of post-translational modification of Hh and Wg
B) Genetic and biochemical analysis of the trafficking of the type I Dpp receptor TKV.
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