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Steven Dooley

About Steven Dooley:
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SEEK ID: https://seek.lisym.org/people/38

Location: Germany

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LiSyM network

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Public web page: http://www.lisym.org

Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III)

The incidence of this life-threatening acute-on-chronic liver failure (ACLF) is increasing, and early detection and cure are urgent clinical needs. Pillar III applies a Systems Medicine approach to identify the critical mechanisms of acute-on-chronic liver failure (ACLF) and to foster liver regeneration and repair.

Public web page: Not specified

Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Chronic liver diseases (CLD) progression leads to cirrhosis, often cancer, and ultimately to organ failure and death. Because of the complexity of this scenario, a Systems Medicine approach is chosen to develop strategies to better characterize progression and resolution of fibrosis. Pillar II aims to define key molecular mechanisms and structural changes in tissue architecture during the progression of CLD by visualizing and quantifying at a cellular level, tissue and organ scale.

Public web page: Not specified

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Adenovirusmediated overexpression of bone morphogenetic protein9 promotes methionine choline deficiencyinduced nonalcoholic steatohepatitis in nonobese mice.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract (Expand)

Liver inflammation and macrophage infiltration are critical steps in the progression of nonalcoholic fatty liver to the development of nonalcoholic steatohepatitis. Bone morphogenetic protein9 is a … cytokine involved in the regulation of chemokines and lipogenesis. However, the function of bone morphogenetic protein9 in nonalcoholic steatohepatitis is still unknown. The present study hypothesized that bone morphogenetic protein9 may contribute to steatohepatitis in mice fed a methionine choline deficiency diet (MCD). C57BL/6 mice overexpressing bone morphogenetic protein9 and control mice were fed the MCD diet for 4 weeks. Liver tissue and serum samples were obtained for subsequent measurements. Bone morphogenetic protein9 overexpression exacerbated steatohepatitis in mice on the MCD diet, as indicated by liver histopathology, increased serum alanine aminotransferase activity, aspartate transaminase activity, hepatic inflammatory gene expression and M1 macrophage recruitment. Although bone morphogenetic protein9 overexpression did not affect the expression of profibrogenic genes, including Collagen I (alpha)1 or matrix metalloproteinase (MMP) 9, it did upregulate the expression of transforming growth factorbeta and plasminogen activator inhibitor 1, and downregulated the expression of MMP2. The above results indicate that bone morphogenetic protein9 exerts a proinflammatory role in MCD dietinduced nonalcoholic steatohepatitis.

Authors: Q. Li, B. Liu, K. Breitkopf-Heinlein, H. Weng, Yixin Jiang, P. Dong, Steven Dooley, K. Xu, H. Ding

Date Published: 20th Jul 2019

Journal: Mol Med Rep

TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract (Expand)

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment … is mainly the removal of the causative factor. Transforming growth factor (TGF)-beta is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-beta has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-beta and its upstream and downstream regulatory mechanisms will help to design better TGF-beta based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-beta signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-beta on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-beta. Finally, we discuss new approaches to target the TGF-beta pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

Authors: B. Dewidar, C. Meyer, Steven Dooley, A. N. Meindl-Beinker

Date Published: 11th Nov 2019

Journal: Cells

Editorial: Systems Biology and Bioinformatics in Gastroenterology and Hepatology
LiSyM network

Abstract

Not specified

Authors: Peter Jansen, Kai Breuhahn, Andreas Teufel, Steven Dooley

Date Published: 22nd Nov 2019

Journal: Front. Physiol.

ECM1 stabilizes matrix deposited latent TGF-β to maintain liver homeostasis and prevent fibrogenesis
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Abstract

Not specified

Authors: Seddik Hammad, W Fan, T Liu, W Chen, K Gould, T Longerich, I Haußer-Siller, J Hou, J Jia, B Sun, Steven Dooley

Date Published: 2019

Journal: Not specified

ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice.
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network

Abstract (Expand)

BACKGROUND & AIMS: Activation of transforming growth factor beta (TGFB) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanism of TGFB activation are not clear. We … investigated the role of extracellular matrix protein 1 (ECM1), which interacts with extracellular and structural proteins, in TGFB activation in livers of mice. METHODS: We performed studies with e C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Deltahep). ECM1 or soluble TGFB receptor 2 (TGFBR2) were expressed in livers of mice following injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy liver were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with alphav integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Deltahep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Authors: W. Fan, T. Liu, W. Chen, Seddik Hammad, T. Longerich, Y. Fu, N. Li, Y. He, C. Liu, Y. Zhang, Q. Lian, Jieling Zhao, C. Yan, L. Li, C. Yi, Z. Ling, L. Ma, Jieling Zhao, H. Xu, P. Wang, M. Cong, H. You, Z. Liu, Y. Wang, J. Chen, D. Li, L. Hui, Steven Dooley, J. Hou, J. Jia, B. Sun

Date Published: 27th Jul 2019

Journal: Gastroenterology

P2-LiSyM Intro-v2-SD-0605
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Modified slides 6 and 7

Creator: Steven Dooley

Contributor: Steven Dooley

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P2 LiSyM Introduction-v1-SD-0305
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)
No description specified

Creator: Steven Dooley

Contributor: Steven Dooley

Focused Scores Enable Reliable Discrimination of Small Differences in Steatosis
Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Poster presented at Hünfeld Retreat 2018

Creators: André Homeyer, Seddik Hammad, Lars Ole Schwen, Steven Dooley, Andrea Schenk, Uta Dahmen, Henning Höfener, Yan Gao

Contributor: Lars Ole Schwen

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Liver regeneration in ACLF patients
Chronic Liver Disease Progression (LiSyM-DP - Pillar II), Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III)

confidential, with unpublished data

Creator: Steven Dooley

Contributor: Steven Dooley

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