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Description
Abstract:
Hedgehog (Hh) signaling plays critical roles in pattern formation, embryonic development, and cell growth
control; however, its function(s) in adulthood remain largely unknown although the mylfunction of Hh signaling
causes several types of cancer. Hh signaling has also been shown to be involved in neurodegenerative disease
and shown to regulate the proliferation of neuroal stem cells. It is unknown whether Hh signaling is involved in
Alzheimer’s disease. Transduction of the Hh signal requires the G protein-coupled receptor (GPCR) family
protein Smoothened (Smo) in both insects and mammals. Recent studies have demonstrated that cholesterol
activates Smo through direct interaction and possibly covalent attachment. Whether and how cholesterol
biosynthesis pathway regulates Smo are unclear. We recently discovered that Hh signaling activity maintains
the viability of dopaminergic neurons in Drosophila adult brain. Inactivation of Hh signaling significantly
decreased the lifespan of adult flies. In addition, we identified a non-canonical cholesterol biosynthesis pathway
that critically regulates Smo. We have established a Alzhermer’s disease model by expressing human amyloid
beta (Aβ) in adult flies. We hypothesize that the non-canonical cholesterol biosynthesis pathway plays a role in
compromising the defects caused by Aβ expression. We will determine whether cholesterol biosynthesis protects
dopaminergic neurons in the adult brain and modulates Drosophila lifespan (Aim 1). We will determine whether
cholesterol biosynthesis provide a protective effect in Aβ-induced neurodegeneration of the Alzheimer’s disease
model (Aim 2). Proposed studies use a combination of genetic and biochemical approaches to build on prior
contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study will
provide novel insights into mechanisms of Hh signaling in the protection of neurodegeneration and Alzheimer’s
disease.
Status | Finished |
---|---|
Effective start/end date | 9/1/19 → 1/31/25 |
Funding
- National Institute of General Medical Sciences
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Projects
- 1 Finished
-
Hedgehog Signaling in Development and Metabolism
Jia, J. (PI), Wang, C. (CoI), Vander Kooi, C. (Former CoI) & Zhu, H. (Former CoI)
National Institute of General Medical Sciences
9/1/19 → 1/31/25
Project: Research project