Deregulation of the Sonic Hedgehog (Shh) signal transduction pathway results in a number of human developmental disorders and contributes to a diverse array of tumors. Despite the importance of Shh in human disease, basic questions regarding the biogenesis of Shh remain poorly understood. Here, we propose to elucidate the normal physiology of Shh: how it is processed into its lipid modified form, trafficked and secreted out of the cell to function as both a short-range and long-range signaling molecule. We will approach this question from two directions, initially focusing on the trafficking and secretion of a form of Shh implicated in long-range signaling. Our second approach will be to uncover the various steps in Shh biogenesis that are disrupted by the Shh mutations identified in the human developmental disorder known as holoprosencephaly (HPE). Combined, our approach will identify important steps in the production, trafficking, activity and secretion of Shh. The knowledge gained upon completion of this work could be used to design preventative or curative strategies for the various human pathologies that result from a deregulated Shh pathway.

Public Health Relevance

The long-term goal of our research is to elucidate how the secreted protein Sonic Hedgehog (Shh) contributes to human development, and how this regulation is disrupted in various human pathologies. Prior to achieving these goals, we will first have to understand the normal physiology of Shh: how it is presented to receiving cells and how these cells interpret this signal. The knowledge gained as a result of this work could be used to design preventative or curative strategies for the different human pathologies that result from a deregulated Shh pathway.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
Li, Bin; Giambelli, Camilla; Tang, Bo et al. (2016) Arsenic Attenuates GLI Signaling, Increasing or Decreasing its Transcriptional Program in a Context-Dependent Manner. Mol Pharmacol 89:226-32
Long, Jun; Tokhunts, Robert; Old, William M et al. (2015) Identification of a family of fatty-acid-speciated sonic hedgehog proteins, whose members display differential biological properties. Cell Rep 10:1280-1287
Li, Bin; Fei, Dennis Liang; Flaveny, Colin A et al. (2014) Pyrvinium attenuates Hedgehog signaling downstream of smoothened. Cancer Res 74:4811-21
Fei, Dennis Liang; Koestler, Devin C; Li, Zhigang et al. (2013) Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study. Environ Health 12:58
Fei, Dennis Liang; Sanchez-Mejias, Avencia; Wang, Zhiqiang et al. (2012) Hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Res 72:4449-58
Robbins, David J; Fei, Dennis Liang; Riobo, Natalia A (2012) The Hedgehog signal transduction network. Sci Signal 5:re6
Singh, Samer; Wang, Zhiqiang; Liang Fei, Dennis et al. (2011) Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res 71:4454-63
Fei, Dennis Liang; Li, Hua; Kozul, Courtney D et al. (2010) Activation of Hedgehog signaling by the environmental toxicant arsenic may contribute to the etiology of arsenic-induced tumors. Cancer Res 70:1981-8
Tokhunts, Robert; Singh, Samer; Chu, Tehyen et al. (2010) The full-length unprocessed hedgehog protein is an active signaling molecule. J Biol Chem 285:2562-8
Singh, Samer; Tokhunts, Robert; Baubet, Valerie et al. (2009) Sonic hedgehog mutations identified in holoprosencephaly patients can act in a dominant negative manner. Hum Genet 125:95-103

Showing the most recent 10 out of 12 publications