# Signal Transduction in the Primary Cilium: Hedgehog and Beyond

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

PROJECT SUMMARY / ABSTRACT: The primary cilium is a tiny, immotile antenna-shaped protrusion found
on nearly every cell in the human body. This organelle is essential for organ development and function, serving
as a hub for several critical cell signaling pathways. Perturbing cilia instigates a slew of ciliopathies that include
developmental, sensory, metabolic, and regenerative disorders. While the biological roles of the cilium are
known, it is unclear at a biochemical level how or why the cilium is needed for its constituent cascades to operate.
This prevents an understanding of how the cilium serves any of its biological functions. It also stymies our ability
to control ciliary signaling therapeutically. The goal of the work proposed here is to understand the biochemical
and biophysical principles governing ciliary signal transduction. Rather than relying on conventional genetic and
cell biological approaches in the field, we are harnessing non-traditional biochemical and physiologic tools from
other areas of biology; this includes reconstitution systems and live-cell sensors for key transduction events.
This proposal uses the Hedgehog (Hh) pathway, a model ciliary cascade and fundamental regulator of
embryogenesis and stem cell biology, to address these outstanding questions. At the ciliary membrane, the
seven-transmembrane (7TM) protein Smoothened (SMO) is the pivotal molecule controlling essentially all the
Hh pathway’s biological activities. The following three projects will together uncover the molecules and
mechanisms by which SMO and related ciliary 7TM proteins signal: 1) What are biochemical mechanisms that
regulate SMO activation? This builds on the recent discovery that ion gradients and membrane lipids are key
regulators of the crucial initial steps of Hh signaling. These studies now provide a platform to investigate how
membrane cholesterol, a candidate “messenger” linking upstream pathway events to SMO activity, binds to and
activates SMO. These efforts have also revealed additional SMO regulatory factors, which we will identify
biochemically. 2) How does SMO, once activated, communicate to GLI transcription factors that control
expression of Hh pathway target genes? We will pinpoint SMO’s long-sought immediate downstream effector
in the Hh pathway and test the hypothesis that the cilium serves primarily as a “meeting place” to concentrate
activated pathway components together. 3) How do these regulatory influences operate within the cilium? These
experiments will test the physiological significance of the regulatory factors we identify biochemically, as well as
quantitatively compare and selectively manipulate signal transduction in the ciliary and “cell body” compartments.
Each project also provides stepping stones to investigate related mechanisms that govern 7TM proteins in many
other ciliary signaling cascades. The techniques deployed and principles learned from the Hh cascade will thus
be broadly applicable to other ciliar...

## Key facts

- **NIH application ID:** 9990813
- **Project number:** 5R35GM133672-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Benjamin Myers
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2019-08-07 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990813

## Citation

> US National Institutes of Health, RePORTER application 9990813, Signal Transduction in the Primary Cilium: Hedgehog and Beyond (5R35GM133672-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990813. Licensed CC0.

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