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Understanding the Molecular Pathobio...

Yu, Fabian.

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Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency./
Author:	Yu, Fabian.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	340 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-06, Section: B.
Contained By:	Dissertations Abstracts International80-06B.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10844556
ISBN:	9780438683051

Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency.
Yu, Fabian.

Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 340 p.

Source: Dissertations Abstracts International, Volume: 80-06, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2018.

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

Farber disease (FD) is a devastating Lysosomal Storage Disorder (LSD) caused by mutations in ASAH1, resulting in acid ceramidase (ACDase) deficiency. ACDase deficiency manifests along a broad spectrum but in its classical form patients die during early childhood. Due to the scarcity of cases FD has largely been understudied. To circumvent this, our lab previously generated a mouse model that recapitulates FD. In some case reports, patients have shown signs of visceral involvement, retinopathy and respiratory distress that may lead to death. Beyond superficial descriptions in case reports, there have been no in-depth studies performed to address these conditions. To improve the understanding of FD and gain insights for evaluating future therapies, we performed comprehensive studies on the ACDase deficient mouse. In the visual system, we reported presence of progressive uveitis. Further tests revealed cellular infiltration, lipid buildup and extensive retinal pathology. Mice developed retinal dysplasia, impaired retinal response and decreased visual acuity. Within the pulmonary system, lung function tests revealed a decrease in lung compliance. Mice developed chronic lung injury that was contributed by cellular recruitment, and vascular leakage. Additionally, we report impairment to lipid homeostasis in the lungs. To understand the liver involvement in FD, we characterized the pathology and performed transcriptome analysis to identify gene and pathway changes. We revealed progressive liver injury, inflammation and fibrosis. RNAseq analyses on hepatocytes revealed activation of pathways in inflammation response and cellular recruitment and deactivation of pathways related to lipid metabolism. MCP-1 is an inflammatory chemokine that is dramatically elevated in ACDase deficient mice and humans. To understand the role of MCP-1 in FD, we created and characterized the Asah1P361R/P361R;MCP-1 -/- double mutant mice. Ablation of MCP-1 attenuated disease and provided a modest extension of life from ∼9 weeks to ∼14 weeks of age. The greatest reduction in inflammation was detected in the lung. Decreased inflammation in the Asah1P361R/P361R;MCP-1 -/- mice also resulted in less ceramide accumulation in the lung and liver. Taken together, targeting MCP-1 though not effective in all organs may provide a benefit in combination with other therapies until a cure is available for this debilitating disorder.

ISBN: 9780438683051Subjects--Topical Terms:

518028
Biochemistry.

Understanding the Molecular Pathobiology of Acid Ceramidase Deficiency.
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500 $a Source: Dissertations Abstracts International, Volume: 80-06, Section: B.
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520 $a Farber disease (FD) is a devastating Lysosomal Storage Disorder (LSD) caused by mutations in ASAH1, resulting in acid ceramidase (ACDase) deficiency. ACDase deficiency manifests along a broad spectrum but in its classical form patients die during early childhood. Due to the scarcity of cases FD has largely been understudied. To circumvent this, our lab previously generated a mouse model that recapitulates FD. In some case reports, patients have shown signs of visceral involvement, retinopathy and respiratory distress that may lead to death. Beyond superficial descriptions in case reports, there have been no in-depth studies performed to address these conditions. To improve the understanding of FD and gain insights for evaluating future therapies, we performed comprehensive studies on the ACDase deficient mouse. In the visual system, we reported presence of progressive uveitis. Further tests revealed cellular infiltration, lipid buildup and extensive retinal pathology. Mice developed retinal dysplasia, impaired retinal response and decreased visual acuity. Within the pulmonary system, lung function tests revealed a decrease in lung compliance. Mice developed chronic lung injury that was contributed by cellular recruitment, and vascular leakage. Additionally, we report impairment to lipid homeostasis in the lungs. To understand the liver involvement in FD, we characterized the pathology and performed transcriptome analysis to identify gene and pathway changes. We revealed progressive liver injury, inflammation and fibrosis. RNAseq analyses on hepatocytes revealed activation of pathways in inflammation response and cellular recruitment and deactivation of pathways related to lipid metabolism. MCP-1 is an inflammatory chemokine that is dramatically elevated in ACDase deficient mice and humans. To understand the role of MCP-1 in FD, we created and characterized the Asah1P361R/P361R;MCP-1 -/- double mutant mice. Ablation of MCP-1 attenuated disease and provided a modest extension of life from ∼9 weeks to ∼14 weeks of age. The greatest reduction in inflammation was detected in the lung. Decreased inflammation in the Asah1P361R/P361R;MCP-1 -/- mice also resulted in less ceramide accumulation in the lung and liver. Taken together, targeting MCP-1 though not effective in all organs may provide a benefit in combination with other therapies until a cure is available for this debilitating disorder.
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