Sonic hedgehog (Shh) signaling plays a crucial role in the normal development of many tissues including the hair follicle;however, inappropriate pathway activity is associated with a variety of human birth defects, and up to 25% of human cancers, including cutaneous basal cell carcinomas (BCCs). Human tumors induce hedgehog signaling differently: cell autonomous pathway activation, autocrine stimulation, or paracrine stimulation via the surrounding stroma. Each type of cancer requires the pathway for growth, but differs in the cellular origin of those growth signals, highlighting the emerging need to identify new therapeutic targets and fill gaps in understanding the signaling interactions between tumor and stroma. The goal of ARO46786, now in its 10th year, is to focus on gaps in our understanding of hedgehog signaling during regeneration and tumor formation in order to develop new therapeutic leads. Each of the three aims addresses a particular gap that this project will investigate over the next funding period as we aim to : 1) Determine the role of Polarity Protein signaling in hedgehog signaling by determining epistatic relationships of aPKC in ciliogenesis, determining how aPKC regulates hedgehog signaling, determining aPKC and PI3 kinase crosstalk in the control of hedgehog pathway, and determining the activity of aPKC regulators on BCCs in vitro and in vivo;2) Functionally dissect the hedgehog paracrine signaling network by defining the function of Sox2 and Sox18 in hair regeneration, defining the genetic relationship between Gli, Sox, and noggin, and determining whether Gli and Sox directly regulate gene expression;3) Elucidate novel mechanisms underlying invasive BCCs by confirming mutation breakpoint and altered expression, determining cellular requirements for BCC tumor formation, and identifying the mechanisms of Smo inhibitor resistance in BCCs.

Public Health Relevance

Sonic hedgehog (Shh) signaling plays a crucial role in the normal development of many tissues including the hair follicle;however, inappropriate pathway activity is associated with a variety of human birth defects, and up to 25% of human cancers, including cutaneous basal cell carcinomas (BCCs). The goal of this proposal is to focus on gaps in our understanding of hedgehog signaling during regeneration and tumor formation in order to develop new therapeutic leads by determining the role of Polarity protein signaling in the hedgehog pathway, functionally dissecting the hedgehog paracrine signaling network, and by elucidating the novel mechanisms underlying invasive BCCs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046786-13
Application #
8651889
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (90))
Program Officer
Baker, Carl
Project Start
2000-04-17
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$355,558
Indirect Cost
$135,058
Name
Stanford University
Department
Dermatology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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