東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back

Switch To: Labeled | MARC Mode | ISBD

The Role of Lipids in Pulmonary Alve...

Lee, Elinor.

Linked to FindBook

Google Book

Amazon

博客來

The Role of Lipids in Pulmonary Alveolar Proteinosis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of Lipids in Pulmonary Alveolar Proteinosis./
Author:	Lee, Elinor.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	123 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-05, Section: B.
Contained By:	Dissertations Abstracts International82-05B.
Subject:	Molecular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28153218
ISBN:	9798691228346

The Role of Lipids in Pulmonary Alveolar Proteinosis.
Lee, Elinor.

The Role of Lipids in Pulmonary Alveolar Proteinosis. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 123 p.

Source: Dissertations Abstracts International, Volume: 82-05, Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2020.

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

Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome that has no cure and no FDA approved therapies. It is characterized by the accumulation of surfactant within alveoli due to disruption of granulocyte-macrophage colony stimulating factor (GM-CSF) signaling. The pathogenic mechanism that underlies PAP remains unknown. Early studies suggested that PAP resulted from dysfunction in phospholipid homeostasis that led to the accumulation of phospholipid-enriched surfactant. However, more recent studies suggest that PAP pathogenesis is driven by changes in cholesterol homeostasis that may be linked to alveolar macrophages. The goal of this dissertation is to investigate the molecular mechanisms that lead to lipid dysregulation in PAP. First, we examined the lipid content of both alveolar macrophages and type 2 epithelial cells, two primary cells involved in surfactant homeostasis in a mouse model of PAP (Abcg1-/- mice). Compared to wildtype animals, Abcg1-/- mice had increased lipid deposition in both alveolar macrophages and type 2 epithelial cells, suggesting both cells are involved in the pathogenesis of PAP. Next, we observed that PAP patients who were treated with a cholesterol-lowering agent, statin, demonstrated improvements in their lung disease. We then treated Csf2rb-/- mice, another PAP mouse model, with a statin and found that they had improvement in their lung disease due to increased efflux of cholesterol from alveolar macrophages. Finally, we utilized lipidomic analysis and mass spectrometry to measure lipid composition of PAP alveolar macrophages. We found that compared to non-PAP alveolar macrophages, PAP alveolar macrophages were enriched in phosphatidylcholine (PC) and cholesterol ester (CE). Furthermore, clinical improvement in treated PAP patients was associated with a decrease in PC and CE classes, indicating that levels of these lipids correlated with the severity of the disease.Our studies demonstrate that disruption of both phospholipid and cholesterol homeostasis contributes to the pathogenesis of PAP. This new mechanistic insight has provided us with a better understanding of the pathophysiology of PAP and will be instrumental in our endeavor to find novel therapeutic targets and ultimately a cure for these patients.

ISBN: 9798691228346Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Pulmonary alveolar proteinosis

The Role of Lipids in Pulmonary Alveolar Proteinosis.
LDR:03397nmm a2200349 4500 001 2285315
005 20211129133336.5
008 220723s2020 ||||||||||||||||| ||eng d
020 $a 9798691228346
035 $a (MiAaPQ)AAI28153218
035 $a AAI28153218
040 $a MiAaPQ $c MiAaPQ
100 1 $a Lee, Elinor. $3 3564609
245 1 4 $a The Role of Lipids in Pulmonary Alveolar Proteinosis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 123 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-05, Section: B.
500 $a Advisor: Aguiar Vallim, Elizabeth.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome that has no cure and no FDA approved therapies. It is characterized by the accumulation of surfactant within alveoli due to disruption of granulocyte-macrophage colony stimulating factor (GM-CSF) signaling. The pathogenic mechanism that underlies PAP remains unknown. Early studies suggested that PAP resulted from dysfunction in phospholipid homeostasis that led to the accumulation of phospholipid-enriched surfactant. However, more recent studies suggest that PAP pathogenesis is driven by changes in cholesterol homeostasis that may be linked to alveolar macrophages. The goal of this dissertation is to investigate the molecular mechanisms that lead to lipid dysregulation in PAP. First, we examined the lipid content of both alveolar macrophages and type 2 epithelial cells, two primary cells involved in surfactant homeostasis in a mouse model of PAP (Abcg1-/- mice). Compared to wildtype animals, Abcg1-/- mice had increased lipid deposition in both alveolar macrophages and type 2 epithelial cells, suggesting both cells are involved in the pathogenesis of PAP. Next, we observed that PAP patients who were treated with a cholesterol-lowering agent, statin, demonstrated improvements in their lung disease. We then treated Csf2rb-/- mice, another PAP mouse model, with a statin and found that they had improvement in their lung disease due to increased efflux of cholesterol from alveolar macrophages. Finally, we utilized lipidomic analysis and mass spectrometry to measure lipid composition of PAP alveolar macrophages. We found that compared to non-PAP alveolar macrophages, PAP alveolar macrophages were enriched in phosphatidylcholine (PC) and cholesterol ester (CE). Furthermore, clinical improvement in treated PAP patients was associated with a decrease in PC and CE classes, indicating that levels of these lipids correlated with the severity of the disease.Our studies demonstrate that disruption of both phospholipid and cholesterol homeostasis contributes to the pathogenesis of PAP. This new mechanistic insight has provided us with a better understanding of the pathophysiology of PAP and will be instrumental in our endeavor to find novel therapeutic targets and ultimately a cure for these patients.
590 $a School code: 0031.
650 4 $a Molecular biology. $3 517296
650 4 $a Medicine. $3 641104
650 4 $a Pathology. $3 643180
653 $a Pulmonary alveolar proteinosis
653 $a Lipid dysregulation
653 $a Pathogenesis
690 $a 0307
690 $a 0564
690 $a 0571
710 2 $a University of California, Los Angeles. $b Molec, Cell, & Integ Physiology 0568. $3 3181612
773 0 $t Dissertations Abstracts International $g 82-05B.
790 $a 0031
791 $a Ph.D.
792 $a 2020
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28153218