Mediators of hedgehog signaling pathways, compositions and uses related thereto

Abstract

The present invention makes available methods and reagents for inducing activation of a hedgehog pathway in a cell or tissue comprising contacting the cell with a hedgehog agonist, such as a small molecule, in a sufficient amount to achieve a therapeutic result. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal ptc pathway or agonizing smoothened or hedgehog activity.

Description

BACKGROUND OF THE INVENTION Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. The physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinsic lineage and cell-extrinsic signaling. Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diverse cell types during tissue differentiation (Davidson, E., (1990) Development 108: 365-389; Gurdon, J. B., (1992) Cell 68: 185-199; Jessell, T. M. et al., (1992) Cell 68: 257-270). The effects of developmental cell interactions are varied. Typically, responding cells are diverted from one route of cell differentiation to another by inducing cells that differ from both the uninduced and induced states of the responding cells (inductions). Sometimes cells induce their neighbors to differentia...

AI Technical Summary

Benefits of technology

The present invention makes available methods and reagents for activating the hedgehog signalling pathway of a cell, e.g., upregulating the hedgehog pathway in a normal cell or modulating growth states resulting from deactivation of the hedgehog signaling pathway, such as ptc gain-of-function, hedgehog loss-of-function, or a smoothened loss-of-function, comprising contacting the cell with an agent, such as a small molecule, in a sufficient amount to modulate the growth state, for example, to reverse or control cell death or growth inhibition, e.g., to antagonize a normal ptc function, agonize a normal hedgehog function, or agonize smoothened function. In certain embodiments of the present invention, a hedgehog pathway agonist, according to the present invention, increases hedgehog-dependent transcriptional activation, such as expression of a ptc or gli gene (particularly Gli-1) but is inhibited by the hedgehog antagonist jervine. In certain preferred embodiments, the agonist upregulates expression of a gli gene by at least 5%, at least 10%, at least 20%, or even at least about 50% relative to a control in the absence of the agonist. The coding sequence...

Problems solved by technology

While not wishing to be bound by any particular theory, the agonist may exert such activity by binding to smoothened or a complex including smoothened, or otherwise disrupts a patched-smoothened complex.

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