Project Details
Description
Hepatic stellate cell (HSC) activation encompasses aphenotype that includes enhanced migration,
proliferation, and matrix deposition. Migration is critical for coordinately situating HSC for matrix deposition
and development of cirrhosis. Our Long-Term Objectives are to understand the molecular underpinnings of
HSC biology that lead to cirrhosis with the goal of identifying therapeutic targets. Recently,we identified a
critical role of synectin in the process of HSC migration and fibrosis. Synectin is a cytosolic protein that
mediates signal transduction, vesicle trafficking, and ultimately gene expression. Synectin is chosen for this
proposal as a significant protein warranting detailed investigation because, as we demonstrate, it is
upregulated in human cirrhosis and is required for murine fibrogenesis. Mechanistically, we implicate synectin
inHSC migration through both short term receptor signaling as well as longer term epigenetic regulation of
gene expression networks. Our preliminary data show that depletion of HSC synectin reduces migration
signaling downstream of the receptor tyrosine kinase, platelet derived growth factor receptor alpha
(PDGFRα); attenuates transcription of a set of HSC activation genes including one that encodes the
multifunctional signaling protein, IGFBP3 (insulin growth factor binding protein-3); and abrogates murine
fibrosis in vivo. These important observations have led us to propose the central hypothesis that synectin
increases HSC migration and fibrosis by promoting PDGFRα signaling and by regulating a network of genes
that include IGFBP3. This hypothesis leads to the following Specific Aims: 1) Synectin promotes HSC
migration by regulating PDGFRα targeting and signal activation. Aim 1a will determine how synectin recruits
and binds specific vesicle trafficking proteins that maintain PDGFRα protein levels, target the protein to
endosomes and activate migration signaling. Aim 1b will uncover how disruption of synectin function leads to
autophagic degradation of PDGFRα and attenuated HSC migration. 2) Synectin epigenetically controls
IGFBP3 gene expression to promote HSC migration. Aim 2a will identify how synectin regulates a specific
histone methyl transferase, EZH2 and how this governs IGFBP3 gene expressionthrough histone
methylation. Aim 2b will determine how IGFBP3 production stimulates HSC migration. 3) Synectin regulates
fibrosis in vivo. Aim 3a will use a novel fibrosis regression model in mice with HSC selective modifications to
synectin and PDGFRα to further ascertain the proposed role of these proteins in vivo. Aim 3b will use a
synectin neutralizing peptide that selectively targets HSC in coordination with magnetic resonance
elastography (MRE) imaging, and mice with genetic deletion of IGFBP3 to elucidate how synectin promotes
fibrosis in vivo. In total, this proposal will utilize conceptually and technically innovative approaches and
concepts to test a novel hypothesis pertaining to synectin as a “master regulator” of HSC signals that lead to
migration and fibrosis.
RELEVANCE (See instructions):
Liver injury from alcohol and other etiologies can culminate in cirrhosis with significant associated morbidity
and mortality.
Status | Active |
---|---|
Effective start/end date | 5/1/19 → 4/30/25 |
Funding
- National Institute on Alcohol Abuse and Alcoholism: $357,750.00
- National Institute on Alcohol Abuse and Alcoholism: $357,750.00
- National Institute on Alcohol Abuse and Alcoholism: $357,750.00
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