Mechanisms of Sonic Hedgehog Signal Transduction

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Stacey Kathryn Ogden
Organization: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
Fiscal Year: 2024
Award: $500,500
Funding agency: National Institute of General Medical Sciences

PROJECT SUMMARY
The evolutionarily conserved Sonic Hedgehog (SHH) signaling pathway governs tissue morphogenesis during
development and contributes to tissue homeostasis in adults. Alteration of pathway activity drives
developmental disorders including Holoprosencephaly (HPE), Pallister-Hall Syndrome and Basal Cell Nevus
syndrome. Inappropriate activation of signaling post-developmentally is frequently associated with cancer,
being causative in basal cell carcinoma and medulloblastoma, and implicated as a survival factor in a range of
additional tumor types. As such, there is significant interest and therapeutic potential in defining the
mechanisms governing SHH pathway activity. My laboratory’s long-term goal is to define the regulatory
processes governing SHH pathway activity during development and use this knowledge to identify
opportunities for targeting inappropriate SHH signaling in disease. Over the next 5 years, we will continue to
work toward this goal by interrogating and defining the molecular mechanisms controlling pivotal regulatory
steps of the SHH signal transduction cascade. We are focused on elucidating 1) how SHH ligand release and
transport are controlled to establish a morphogen gradient, 2) how SMO activation is controlled and how it
coordinates its activity with other G protein coupled receptors at the primary cilium, and 3) how GLI
transcriptional activator induction and destabilization are coordinated to assure an appropriate transcriptional
response.

Terms: <21+ years old><Adult><Adult Human><Autoregulation><Basal Cell Epithelioma><Basal Cell Nevus Syndrome><Basal cell carcinoma><Basiloma><Body Tissues><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cilia><Development><Developmental Process><Disease><Disorder><Fifth Phacomatosis><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Gene Transcription><Genetic Transcription><Goals><Gorlin Syndrome><Gorlin syndrome 2><Gorlin-Goltz Syndrome><Hall syndrome 2><Hedgehog (Hh) signal transduction pathway><Holoprosencephaly><Homeostasis><Intracellular Communication and Signaling><Knowledge><Laboratories><Ligands><Malignant Neoplasms><Malignant Tumor><Medulloblastoma><Methods><Molecular><Morphogenesis><Nevoid Basal Cell Carcinoma Syndrome><Organ><Pallister-Hall syndrome><Pathway interactions><Physiological Homeostasis><Process><RNA Expression><Research><Rodent Ulcer><SHH><SHH gene><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Site><Sonic Hedgehog><Sonic Hedgehog (Shh) Pathway><Sonic Hedgehog Pathway><Syndrome><Therapeutic><Tissues><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Work><adulthood><biological signal transduction><cellular targeting><congenital hypothalamic hamartoblastoma><developmental><developmental disease><developmental disorder><differentiation factors><hamartopolydactyly syndrome><hedgehog signal transduction><hedgehog signaling><hedgehog signaling pathway><hereditary cutaneomandibular polyoncosis><hh signal transduction><hh signaling pathway><hypothalamic hamartoblastoma syndrome><hypothalamic hamartoblastoma-hyperphalangeal hypoendocrine-hypoplastic anus (4H) syndrome><hypothalamic hamartoblastoma-hypopituitarism-imperforate anus-postaxial polydactyly syndrome><interest><jaw cysts-basal cell tumors-skeletal anomalies syndrome><malignancy><microphallus-imperforate anus-syndactyly-hamartoblastoma-abnormal lung lobulation-polydactyly (MISHAP) syndrome><microphallus-imperforate anus-syndactyly-hamartoblastoma-abnormal lung lobulation-polydactyly syndrome><morphogenetic process><morphogenic factors><morphogens><multiple basal-cell carcinoma syndrome multiple basal-cell nevus syndrome><multiple hereditary cutaneomandibular polyoncosis><multiple nevoid basal-cell carcinoma syndrome><multiple nevoid basal-cell epithelioma-jaw cysts-bifid rib syndrome><neoplasm/cancer><nevoid basal-cell epithelioma-jaw cysts-bifid rib syndrome><novel><odontogenic keratocytosis-skeletal anomalies syndrome><pathway><renal-anal-lung-polydactyly-hamartoblastoma (RALPH) syndrome><renal-anal-lung-polydactyly-hamartoblastoma syndrome><response><smoothened signaling pathway><transcription co-activator><transcriptional co-activator><tumor>