# Understanding Patched1 protein and lipid interactions in cilia

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $52,694

## Abstract

PROJECT SUMMARY/ABSTRACT
 Spatiotemporal regulation of signaling molecules is critical for development and adult tissue homeostasis. The
Hedgehog pathway, which is conserved across metazoan animals, controls cell proliferation, differentiation,
migration, and stem cell maintenance. In vertebrates, Hedgehog signals are transduced through primary cilia
that project from the surface of most cells, including cells in cancers that are driven by misactivation of the
Hedgehog pathway. The tumor suppressor Patched1 localizes to cilia and inhibits Smoothened, a Hedgehog
pathway activator. Upon pathway activation, Patched1 leaves cilia and allows Smoothened to activate the
downstream Hedgehog transcriptional program. How Patched1 localizes to cilia and inhibits Smoothened remain
unknown. The central hypothesis of this proposal is that a dynamic network of protein interactions allow Patched1
to accumulate in cilia and regulate the ciliary lipid microenvironment to inhibit Hedgehog signal transduction. To
test this, the objective of this proposal is to define the ciliary protein interactions necessary for localization of
Patched1 to the cilia, and to determine if Patched1 regulates Smoothened by regulating the ciliary lipid
microenvironment.
 To address the gaps in our understanding of Hedgehog signaling, I will leverage recent technical advances
in proteomic proximity-labeling mass spectrometry, lipidomic mass spectrometry, and functional genomics using
novel model systems I have generated for this proposal. In Aim 1, I will interrogate 5 protein interactors of
Patched1 that are associated with human disease and may underlie Patched1 accumulation and activity in
primary cilia. In Aim 2, I will define the impact of Patched1 on the ciliary lipid microenvironment. Combined, these
aims will elucidate the biochemical mechanism by which Patched1 regulates Hedgehog signaling. Hedgehog
pathway misactivation drives medulloblastoma, the most common pediatric brain tumor, and basal cell
carcinoma, the most common cancer in the United States. Thus, this proposal will incorporate Hh-associated
cancer cell lines to determine if ciliary proteins and lipids underlying Patched1 functions are conserved across
developmental and disease contexts. In sum, understanding how Patched1, the most recurrently mutated gene
in Hh-associated cancers, inhibits Hedgehog signaling will provide significant insights into human biology and
potentially provide avenues for novel therapies.

## Key facts

- **NIH application ID:** 10688019
- **Project number:** 5F30CA265147-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Vikas daggubati
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $52,694
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10688019

## Citation

> US National Institutes of Health, RePORTER application 10688019, Understanding Patched1 protein and lipid interactions in cilia (5F30CA265147-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10688019. Licensed CC0.

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