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Investigating the Role of Epidermal ...

Dayal, Simran,

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Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms // Simran Dayal.
作者:	Dayal, Simran,
面頁冊數:	1 electronic resource (159 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
標題:	Bioengineering. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30816236
ISBN:	9798381378269

Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms /
Dayal, Simran,

Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms /Simran Dayal. - 1 electronic resource (159 pages)

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

The inability of adult vascular smooth muscle cells (SMCs) to facilitate elastic matrix regeneration and repair renders it extremely difficult to reverse the pathophysiology of abdominal aortic aneurysms (AAAs), which are localized aortic expansions characterized by severe and naturally irreversible elastic fiber degradation by locally overexpressed matrix metalloproteases (MMPs). Such MMP overexpression is an outcome of chronic inflammatory responses initiated by the activation of several medial SMC signaling cascades within the aorta upon multifactorial insults to the vessel wall. Currently, the management of AAAs is limited to risky open or endovascular surgery on large, rupture imminent AAAs. There are no other established drug-based treatments for AAAs, especially to stabilize or reverse small (< 5.5 cm diameter), growing AAAs, and none that can regenerate, or repair degraded elastic matrix structures in the AAA wall. Towards identifying a new therapeutic target, one of the signaling pathways which is not well understood in the context of AAA etiology and pathophysiology is the role of epidermal growth factor receptor (EGFR). In this work, we have identified and established a novel molecular target (EGFR) and its mechanism of action through which the elastic matrix breakdown likely occurs to prompt AAA progression.The overall goal of this dissertation research is to investigate the potential anti-proteolytic and pro-elastogenic benefits that can be achieved by targeting the novel, identified molecular target of EGFR in-vitro. Our results indicate that EGFR plays a significant role in the disease progression within the aneurysmal SMC milieu via the activation through an inflammatory stimulus, namely neutrophil elastase. Activation of EGFR via neutrophil elastase triggers the proteolytic behavior of MMPs, which promotes elastic fiber degradation. Moreover, this work also establishes the efficacy of a cancer drug, afatinib, for the very first time to demonstrate the anti-MMP and elastin regeneration prospects via the effective inhibition of the EGFR pathway in aneurysmal SMCs. Lastly, our studies establish the development, characterization, and release kinetics of afatinib loaded biodegradable and biocompatible polymer nanoparticles. Overall, this body of work provides initial evidence of improved elastic matrix homeostasis and regeneration attainable by targeting the novel EGFR pathway within the AAA inflammatory milieu. This work will help in defining an innovative approach through which the AAA disease progression can be reversed to provide a regenerative stimulus for elastic matrix repair. Additionally, establishing EGFR as a molecular target in the aneurysmal cells will provide an opportunity to develop EGFR-targeted, minimally invasive nanotherapies which can eventually open doors for small AAA repair at an earlier diagnosis stage.

English

ISBN: 9798381378269Subjects--Topical Terms:

657580
Bioengineering.
Subjects--Index Terms:

Abdominal aortic aneurysms

Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms /
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520 $a The inability of adult vascular smooth muscle cells (SMCs) to facilitate elastic matrix regeneration and repair renders it extremely difficult to reverse the pathophysiology of abdominal aortic aneurysms (AAAs), which are localized aortic expansions characterized by severe and naturally irreversible elastic fiber degradation by locally overexpressed matrix metalloproteases (MMPs). Such MMP overexpression is an outcome of chronic inflammatory responses initiated by the activation of several medial SMC signaling cascades within the aorta upon multifactorial insults to the vessel wall. Currently, the management of AAAs is limited to risky open or endovascular surgery on large, rupture imminent AAAs. There are no other established drug-based treatments for AAAs, especially to stabilize or reverse small (< 5.5 cm diameter), growing AAAs, and none that can regenerate, or repair degraded elastic matrix structures in the AAA wall. Towards identifying a new therapeutic target, one of the signaling pathways which is not well understood in the context of AAA etiology and pathophysiology is the role of epidermal growth factor receptor (EGFR). In this work, we have identified and established a novel molecular target (EGFR) and its mechanism of action through which the elastic matrix breakdown likely occurs to prompt AAA progression.The overall goal of this dissertation research is to investigate the potential anti-proteolytic and pro-elastogenic benefits that can be achieved by targeting the novel, identified molecular target of EGFR in-vitro. Our results indicate that EGFR plays a significant role in the disease progression within the aneurysmal SMC milieu via the activation through an inflammatory stimulus, namely neutrophil elastase. Activation of EGFR via neutrophil elastase triggers the proteolytic behavior of MMPs, which promotes elastic fiber degradation. Moreover, this work also establishes the efficacy of a cancer drug, afatinib, for the very first time to demonstrate the anti-MMP and elastin regeneration prospects via the effective inhibition of the EGFR pathway in aneurysmal SMCs. Lastly, our studies establish the development, characterization, and release kinetics of afatinib loaded biodegradable and biocompatible polymer nanoparticles. Overall, this body of work provides initial evidence of improved elastic matrix homeostasis and regeneration attainable by targeting the novel EGFR pathway within the AAA inflammatory milieu. This work will help in defining an innovative approach through which the AAA disease progression can be reversed to provide a regenerative stimulus for elastic matrix repair. Additionally, establishing EGFR as a molecular target in the aneurysmal cells will provide an opportunity to develop EGFR-targeted, minimally invasive nanotherapies which can eventually open doors for small AAA repair at an earlier diagnosis stage.
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590 $a School code: 0105
650 4 $a Bioengineering. $3 657580
650 4 $a Biomedical engineering. $3 535387
650 4 $a Cellular biology. $3 3172791
653 $a Abdominal aortic aneurysms
653 $a Elastic matrix repair
653 $a Elastin regeneration
653 $a Matrix metalloproteases
653 $a Smooth muscle cells
690 $a 0202
690 $a 0541
690 $a 0379
710 2 $a Lehigh University. $b Bioengineering. $e degree granting institution. $3 3770554
720 1 $a Ramamurthi, Anand $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 85-07B.
790 $a 0105
791 $a Ph.D.
792 $a 2024
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30816236