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Inhibition of Thrombospondin-1 and t...

Min-Debartolo, Jessica Haewon.

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Inhibition of Thrombospondin-1 and the Signal Transducer and Activator of Transcription 3 as Independent Approaches to Attenuate Hepatic Fibrosis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Inhibition of Thrombospondin-1 and the Signal Transducer and Activator of Transcription 3 as Independent Approaches to Attenuate Hepatic Fibrosis./
作者:	Min-Debartolo, Jessica Haewon.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	147 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13420431
ISBN:	9780438949072

Inhibition of Thrombospondin-1 and the Signal Transducer and Activator of Transcription 3 as Independent Approaches to Attenuate Hepatic Fibrosis.
Min-Debartolo, Jessica Haewon.

Inhibition of Thrombospondin-1 and the Signal Transducer and Activator of Transcription 3 as Independent Approaches to Attenuate Hepatic Fibrosis. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 147 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--Boston University, 2019.

This item must not be sold to any third party vendors.

Non-alcoholic steatohepatitis (NASH) is the most severe stage of non-alcoholic fatty liver disease (NAFLD) with extensive fibrosis, inflammation and steatosis. To date, there are no approved therapies for NAFLD/NASH. To identify novel therapeutic targets against hepatic fibrosis, we investigated the role of thrombospondin-I (TSP-1), a protein that regulates transforming growth factor beta 1 (TGF-β1) signaling and subsequent effects on fibrosis, angiogenesis, and inflammation. We first determined that shRNA-mediated TSP-1 ablation caused attenuated expression of fibrotic markers in activated primary human hepatic stellate cells (HSCs), which are the major myofibroblast precursor cells in the liver. To investigate whether TSP-1 has a role in NASH in vivo, we examined the effect of TSP-1 genetic deficiency in a mouse model that utilizes a choline-deficient L-amino acid defined high fat diet (CDAHFD). We demonstrated that CDAHFD-fed TSP-1-deficient mice were less prone to hepatic fibrosis, as indicated by histology and reduced expression of inflammation and fibrosis mRNA markers. In addition, we observed that serum lipid levels were lower in CDAHFD-fed TSP-1-deficient mice. Transcriptomic analysis of hepatic mRNA from TSP-1 deficient mice fed control and CDAHFD diets revealed upregulation of the peroxisome proliferator-activator receptor alpha (PPARα) pathway, which is involved in fatty acid metabolism and inflammation in the liver. Published studies indicate that PPARα activation alleviates NAFLD/NASH symptoms in mouse models and patients. Our results reveal a previously unknown relationship between TSP-1 and PPARα and suggest that TSP-1 could be a candidate target for NASH treatment. In a second set of studies, we investigated the molecular pathways involved in activation of primary human HSCs. We performed transcriptomic analysis of TGF-β1activated human HSCs and also characterized the anti-fibrotic mechanisms of the bromodomain inhibitor JQ1, which is known to attenuate fibrosis in experimental models. Our transcriptomic analysis identified an activated signal transducer and activator of transcription 3 (STAT3) signature in TGF-β1-treated HSCs. We determined that Cpd188-mediated STAT3 inhibition promotes HSC apoptosis, enabling resolution of fibrosis. STAT3 overexpression attenuated Cpd188-mediated apoptosis. Our findings highlight an important role for STAT3 in HSC activation. Therefore, STAT3 inhibition constitutes a promising direction for hepatic fibrosis treatment.

ISBN: 9780438949072Subjects--Topical Terms:

634543
Pharmacology.

Inhibition of Thrombospondin-1 and the Signal Transducer and Activator of Transcription 3 as Independent Approaches to Attenuate Hepatic Fibrosis.
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