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The Role of Exosomes in Complement A...

Huang, Chao.

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The Role of Exosomes in Complement Activation and Development of Diabetic Retinopathy.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of Exosomes in Complement Activation and Development of Diabetic Retinopathy./
Author:	Huang, Chao.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	116 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-03, Section: B.
Contained By:	Dissertations Abstracts International80-03B.
Subject:	Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10841240
ISBN:	9780438332324

The Role of Exosomes in Complement Activation and Development of Diabetic Retinopathy.
Huang, Chao.

The Role of Exosomes in Complement Activation and Development of Diabetic Retinopathy. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 116 p.

Source: Dissertations Abstracts International, Volume: 80-03, Section: B.

Thesis (Ph.D.)--Michigan State University, 2018.

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

Diabetic Retinopathy (DR) is a vision-threatening microvascular complication of diabetes, and more than 50% of diabetic patients develop some degree of retinopathy ten years after the onset of the disease (1). With prevalence of diabetes, DR is a major cause of vision impairment among working age adults and is affecting approximately 4.2 million people in the US and 93 million worldwide, despite remarkable advancement in the diagnostic tools and treatments (2). While progress has been made, detailed molecular mechanisms underlying pathogenesis of DR have not yet been fully deciphered. A number of studies imply that there is a link between progression of DR and complement dysregulation (3). The aim for this dissertation is to provide a novel molecular link connecting complement activation with retinal vascular impairment associated with diabetes. Our studies revealed that extracellular vesicles such as exosomes associate with immunoglobulins in plasma and activate complement pathway, which contributes to the increase in retinal vascular permeability in diabetes. First, we investigated the hypothesis that plasma exosomes activate complement pathway and contribute to retinal vascular damage. We demonstrated that IgG-laden exosomes bind and activate classical complement protein C1 in plasma. Exosome quantification showed an increased number of IgG-laden plasma exosomes in diabetes that may results in greater complement activation. An immunoglobulin deficient mouse model (IgM-KO) showed reduced level of exosome-induced complement activation compared to C57bl/6J mice. Importantly, diabetic IgM-KO mouse model demonstrated a greatly reduced level of retinal vascular permeability as compared to diabetic C57bl/6J. Second, we investigate the hypothesis that exosome-induced complement activation contributes to the increase in membrane attack complex (MAC) deposition and cytolytic damage of retinal endothelium in DR. We demonstrated that diabetic, but not control rat plasma induces MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Removal of the exosomes from diabetic plasma abrogated MAC deposition and cytolytic damage in HRECs. Taken together, these findings suggest a novel mechanism in which plasma exosomes activate complement cascade and contribute to the pathogenesis of DR. This may provide a novel therapeutic strategy for treating DR.

ISBN: 9780438332324Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

Complement system

The Role of Exosomes in Complement Activation and Development of Diabetic Retinopathy.
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500 $a Source: Dissertations Abstracts International, Volume: 80-03, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Busik, Julia V.
502 $a Thesis (Ph.D.)--Michigan State University, 2018.
506 $a This item must not be sold to any third party vendors.
520 $a Diabetic Retinopathy (DR) is a vision-threatening microvascular complication of diabetes, and more than 50% of diabetic patients develop some degree of retinopathy ten years after the onset of the disease (1). With prevalence of diabetes, DR is a major cause of vision impairment among working age adults and is affecting approximately 4.2 million people in the US and 93 million worldwide, despite remarkable advancement in the diagnostic tools and treatments (2). While progress has been made, detailed molecular mechanisms underlying pathogenesis of DR have not yet been fully deciphered. A number of studies imply that there is a link between progression of DR and complement dysregulation (3). The aim for this dissertation is to provide a novel molecular link connecting complement activation with retinal vascular impairment associated with diabetes. Our studies revealed that extracellular vesicles such as exosomes associate with immunoglobulins in plasma and activate complement pathway, which contributes to the increase in retinal vascular permeability in diabetes. First, we investigated the hypothesis that plasma exosomes activate complement pathway and contribute to retinal vascular damage. We demonstrated that IgG-laden exosomes bind and activate classical complement protein C1 in plasma. Exosome quantification showed an increased number of IgG-laden plasma exosomes in diabetes that may results in greater complement activation. An immunoglobulin deficient mouse model (IgM-KO) showed reduced level of exosome-induced complement activation compared to C57bl/6J mice. Importantly, diabetic IgM-KO mouse model demonstrated a greatly reduced level of retinal vascular permeability as compared to diabetic C57bl/6J. Second, we investigate the hypothesis that exosome-induced complement activation contributes to the increase in membrane attack complex (MAC) deposition and cytolytic damage of retinal endothelium in DR. We demonstrated that diabetic, but not control rat plasma induces MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Removal of the exosomes from diabetic plasma abrogated MAC deposition and cytolytic damage in HRECs. Taken together, these findings suggest a novel mechanism in which plasma exosomes activate complement cascade and contribute to the pathogenesis of DR. This may provide a novel therapeutic strategy for treating DR.
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