國立虎尾科技大學 |

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

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms./
作者:	Dayal, Simran.
面頁冊數:	1 online resource (159 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
標題:	Cellular biology. -
電子資源:	click for full text (PQDT)
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. - 1 online resource (159 pages)

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

Thesis (Ph.D.)--Lehigh University, 2024.

Includes bibliographical references

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.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381378269Subjects--Topical Terms:

1148666
Cellular biology.
Subjects--Index Terms:

Abdominal aortic aneurysmsIndex Terms--Genre/Form:

554714
Electronic books.

Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms.
LDR:04305ntm a22003977 4500 001 1148776
005 20240930100144.5
006 m o d
007 cr bn ---uuuuu
008 250605s2024 xx obm 000 0 eng d
020 $a 9798381378269
035 $a (MiAaPQ)AAI30816236
035 $a AAI30816236
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Dayal, Simran. $3 1474832
245 1 0 $a Investigating the Role of Epidermal Growth Factor Receptor in Abdominal Aortic Aneurysms.
264 0 $c 2024
300 $a 1 online resource (159 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
500 $a Advisor: Ramamurthi, Anand.
502 $a Thesis (Ph.D.)--Lehigh University, 2024.
504 $a Includes bibliographical references
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.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2024
538 $a Mode of access: World Wide Web
650 4 $a Cellular biology. $3 1148666
650 4 $a Biomedical engineering. $3 588770
650 4 $a Bioengineering. $3 598252
653 $a Abdominal aortic aneurysms
653 $a Elastic matrix repair
653 $a Elastin regeneration
653 $a Matrix metalloproteases
653 $a Smooth muscle cells
655 7 $a Electronic books. $2 local $3 554714
690 $a 0202
690 $a 0541
690 $a 0379
710 2 $a Lehigh University. $b Bioengineering. $3 1466354
710 2 $a ProQuest Information and Learning Co. $3 1178819
773 0 $t Dissertations Abstracts International $g 85-07B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30816236 $z click for full text (PQDT)