東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Targeting Organic Anion Transporting...

Abdullahi, Wazir.

FindBook

Google Book

Amazon

博客來

Targeting Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Targeting Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier./
作者:	Abdullahi, Wazir.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	220 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-08, Section: B.
Contained By:	Dissertations Abstracts International80-08B.
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13424880
ISBN:	9780438809772

Targeting Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier.
Abdullahi, Wazir.

Targeting Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 220 p.

Source: Dissertations Abstracts International, Volume: 80-08, Section: B.

Thesis (Ph.D.)--The University of Arizona, 2019.

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

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) have been investigated as strategies that can improve blood-to-brain drug transport and optimize treatment of CNS diseases. Indeed, direct pharmacological inhibition of P-gp using small molecules or selective regulation by targeting intracellular signaling pathways has been extensively explored; however, these approaches have been largely unsuccessful due to toxicity concerns and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with hypoxia-reoxygenation (H/R) component such as ischemic stroke, can be achieved by targeting of endogenous BBB transporters that mediate blood-to-brain uptake of their substrates. We have focused our work on organic anion transporting polypeptide 1a4 (Oatp1a4), the primary drug transporting Oatp isoform at the BBB. Oatp1a4 has demonstrated blood-to-brain transport of drugs with neuroprotective properties such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins). Development of Oatp1a4 as a transporter target that can be exploited for improved treatment of neurological diseases requires a rigorous characterization of the "molecular machinery" that controls its functional expression at the BBB. Here, we show that activation of activin receptor-like kinase 1 (ALK1), a critical component of the transforming growth factor-β (TGF-β) pathway, using the selective agonist Bone Morphogenetic Protein (BMP)-9 increases Oatp1a4 protein expression in rat brain microvessels in vivo. Additionally, we demonstrate that BMP-9 treatment increases blood-to-brain transport and brain exposure of established Oatp transport substrates (i.e., taurocholate, atorvastatin, pravastatin). Of particular significance, we have elucidated that BMP-9 activates the canonical TGF-β/ALK1 signaling pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report for the first time that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and directly binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Additionally, BMP-9 treatment did not alter expression of tight junction proteins (i.e., occludin, claudin-5) or paracellular "leak" of the vascular marker sucrose, indicating that targeting TGF-β/ALK1 signaling does not adversely affect BBB integrity. Overall, our work provides novel evidence that Oatp1a4 transport activity at the BBB is regulated by TGF-β/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of Oatp substrate drugs. Overall, our results point toward a unique opportunity to optimize drug delivery and improve pharmacotherapy for CNS diseases.

ISBN: 9780438809772Subjects--Topical Terms:

634543
Pharmacology.

Targeting Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier.
LDR:04516nmm a2200313 4500 001 2207260
005 20190916101809.5
008 201008s2019 ||||||||||||||||| ||eng d
020 $a 9780438809772
035 $a (MiAaPQ)AAI13424880
035 $a (MiAaPQ)arizona:16880
035 $a AAI13424880
040 $a MiAaPQ $c MiAaPQ
100 1 $a Abdullahi, Wazir. $3 3434223
245 1 0 $a Targeting Organic Anion Transporting Polypeptide 1a4 (Oatp1a4) for Effective Drug Delivery at the Blood-Brain Barrier.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2019
300 $a 220 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-08, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Ronaldson, Patrick.
502 $a Thesis (Ph.D.)--The University of Arizona, 2019.
506 $a This item must not be sold to any third party vendors.
520 $a Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) have been investigated as strategies that can improve blood-to-brain drug transport and optimize treatment of CNS diseases. Indeed, direct pharmacological inhibition of P-gp using small molecules or selective regulation by targeting intracellular signaling pathways has been extensively explored; however, these approaches have been largely unsuccessful due to toxicity concerns and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with hypoxia-reoxygenation (H/R) component such as ischemic stroke, can be achieved by targeting of endogenous BBB transporters that mediate blood-to-brain uptake of their substrates. We have focused our work on organic anion transporting polypeptide 1a4 (Oatp1a4), the primary drug transporting Oatp isoform at the BBB. Oatp1a4 has demonstrated blood-to-brain transport of drugs with neuroprotective properties such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins). Development of Oatp1a4 as a transporter target that can be exploited for improved treatment of neurological diseases requires a rigorous characterization of the "molecular machinery" that controls its functional expression at the BBB. Here, we show that activation of activin receptor-like kinase 1 (ALK1), a critical component of the transforming growth factor-β (TGF-β) pathway, using the selective agonist Bone Morphogenetic Protein (BMP)-9 increases Oatp1a4 protein expression in rat brain microvessels in vivo. Additionally, we demonstrate that BMP-9 treatment increases blood-to-brain transport and brain exposure of established Oatp transport substrates (i.e., taurocholate, atorvastatin, pravastatin). Of particular significance, we have elucidated that BMP-9 activates the canonical TGF-β/ALK1 signaling pathway in brain microvessels as indicated by increased nuclear translocation of specific Smad proteins associated with signaling mediated by the ALK1 receptor (i.e., pSmad1/5/8). Furthermore, we report for the first time that an activated Smad protein complex comprised of phosphorylated Smad1/5/8 and Smad4 is formed following BMP-9 treatment and directly binds to the promoter of the Slco1a4 gene (i.e., the gene that encodes Oatp1a4). This signaling mechanism causes increased expression of Slco1a4 mRNA. Additionally, BMP-9 treatment did not alter expression of tight junction proteins (i.e., occludin, claudin-5) or paracellular "leak" of the vascular marker sucrose, indicating that targeting TGF-β/ALK1 signaling does not adversely affect BBB integrity. Overall, our work provides novel evidence that Oatp1a4 transport activity at the BBB is regulated by TGF-β/ALK1 signaling and indicates that this pathway can be targeted for control of CNS delivery of Oatp substrate drugs. Overall, our results point toward a unique opportunity to optimize drug delivery and improve pharmacotherapy for CNS diseases.
590 $a School code: 0009.
650 4 $a Pharmacology. $3 634543
690 $a 0419
710 2 $a The University of Arizona. $b Medical Pharmacology. $3 1682535
773 0 $t Dissertations Abstracts International $g 80-08B.
790 $a 0009
791 $a Ph.D.
792 $a 2019
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13424880