# Regulation of Shh Signaling by Cellular Energetics

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $400,237

## Abstract

Project Summary:
The Shh pathway plays critical roles in development, stem cell maintenance and tissue homeostasis.
Deregulated Shh signaling during cerebellar development causes medulloblastoma, the most common
pediatric brain tumors in childhood with presumed cellular origin in granule cell precursors (GCPs). During
postnatal development, GCPs undergo rapid and transient proliferation in the outer external granule layer
(EGL) in response to Shh signaling before differentiating and migrating inward to become granule neurons.
Persistent Shh signaling counters this stereotypic developmental pattern, resulting in disrupted differentiation
and prolonged stay of GCPs in the outer EGL where cerebellar neoplasm is thought to initiate. Therefore,
elucidating the mechanism by which CGP proliferation and differentiation are regulated is important to our
understanding of cerebellar tumorigenesis. Deregulated cellular growth and proliferation are hallmarks of
neoplasms that entail energy-consuming anabolic processes such as protein synthesis and lipogenesis. These
anabolic processes are highly regulated and subject to stringent control by cellular energy sensors. The key
energy sensor that is activated under condition of energy depletion is AMP-activated protein kinase (AMPK).
We discovered that AMPK is a potent inhibitor of Shh signaling in GCPs and primary medulloblastoma cells.
Moreover, AMPK is selectively activated in the inner EGL of the developing cerebellum where Shh signaling is
downregulated and GCPs have begun differentiating. These observations suggest that AMPK may play a
critical role in modulating Shh signaling in GCPs for differentiation, proliferation and tumorigenesis. We will test
this hypothesis by three aims: 1) Elucidate the mechanism by which AMPK activation antagonizes Shh
pathway activity; 2) Determine the role of AMPK in modulating GCP proliferation and differentiation in vivo; 3)
Determine the effect of AMPK activation in Shh-driven medulloblastoma in vivo.

## Key facts

- **NIH application ID:** 10001606
- **Project number:** 5R01NS096899-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** CHIN CHIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,237
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001606

## Citation

> US National Institutes of Health, RePORTER application 10001606, Regulation of Shh Signaling by Cellular Energetics (5R01NS096899-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001606. Licensed CC0.

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