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Molecular and Pharmacological Analys...

Julian, Bina.

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Molecular and Pharmacological Analysis of the Chemokine Receptor CCR6.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Molecular and Pharmacological Analysis of the Chemokine Receptor CCR6./
Author:	Julian, Bina.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
Description:	175 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.
Contained By:	Dissertation Abstracts International78-07B(E).
Subject:	Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10254519
ISBN:	9781369614404

Molecular and Pharmacological Analysis of the Chemokine Receptor CCR6.
Julian, Bina.

Molecular and Pharmacological Analysis of the Chemokine Receptor CCR6. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 175 p.

Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.

Thesis (Ph.D.)--Sackler School of Graduate Biomedical Sciences (Tufts University), 2017.

This thesis advances the molecular understanding of Cys-Cys Chemokine Receptor 6 (CCR6) through mutagenesis studies and the development of CCR6-based tools that measure and modulate receptor function. CCR6 is a G protein-coupled receptor (GPCR) whose signaling influences the behavior of a wide range of cells involved in the inflammatory response. CCR6 has gained attention for its expression on the Th17 cell type, a proinflammatory T cell associated with an ever-growing list of chronic inflammatory diseases. Surprisingly, little is understood about the underlying molecular pharmacology that influences the GPCR functions of CCR6.

ISBN: 9781369614404Subjects--Topical Terms:

634543
Pharmacology.

Molecular and Pharmacological Analysis of the Chemokine Receptor CCR6.
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100 1 $a Julian, Bina. $3 3289510
245 1 0 $a Molecular and Pharmacological Analysis of the Chemokine Receptor CCR6.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2017
300 $a 175 p.
500 $a Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.
500 $a Advisers: Alan S. Kopin; Theoharis C. Theoharides.
502 $a Thesis (Ph.D.)--Sackler School of Graduate Biomedical Sciences (Tufts University), 2017.
520 $a This thesis advances the molecular understanding of Cys-Cys Chemokine Receptor 6 (CCR6) through mutagenesis studies and the development of CCR6-based tools that measure and modulate receptor function. CCR6 is a G protein-coupled receptor (GPCR) whose signaling influences the behavior of a wide range of cells involved in the inflammatory response. CCR6 has gained attention for its expression on the Th17 cell type, a proinflammatory T cell associated with an ever-growing list of chronic inflammatory diseases. Surprisingly, little is understood about the underlying molecular pharmacology that influences the GPCR functions of CCR6.
520 $a To understand the Galphai protein-mediated signaling of the WT receptor, I utilized well-established in vitro luciferase reporter assays in combination with the HEK293 cell model. This assay allowed us to observe the constitutive activity of the WT CCR6 receptor and measure a subnanomolar potency (0.73nM) of its cognate ligand Cys-Cys Chemokine Ligand 20 (CCL20). Furthermore, this assay enabled us to compare and contrast the pharmacological properties of naturally occurring and engineered mutations in CCR6.
520 $a To understand the susceptibility of the CCR6 protein sequence to activating mutations, I performed mutagenesis studies across three conserved regions and the C-terminus of CCR6, which identified 12 amino acids susceptible to activating mutations. Notably, two mutant receptors V255A6.36 and I256A6.37 exhibited triple the basal activity of the WT receptor while maintaining comparable ligand potencies. Constitutively active mutants with these properties are useful tools for drug screening and characterization, therefore I utilized these receptors to characterize two small molecules. Tests found both compounds to be CCR6 inhibitors, with one exhibiting inverse agonists properties.
520 $a GWAS studies have linked CCR6 non-coding polymorphisms with several chronic inflammatory diseases including (e.g. Crohn's Disease, Rheumatoid Arthritis), however naturally occurring missense mutations within CCR6 have yet to be characterized. I characterized the five most frequent CCR6 variants (A89T, A150V, R155W, G345S, A369V) and found them all to be loss-of-function, with A150V and R155W exhibiting a pronounced loss of basal activity and A89T exhibiting a decreased surface expression.
520 $a To understand if mutations within CCR6 affect the ability to recruit beta arrestin, I utilized the bioluminescence resonance energy transfer (BRET) technique. A set including the five loss-of-function missense variants and three constitutively active mutants (V255A, I256A, T98P) was evaluated against the WT receptor. All five naturally occurring variants did not perturb beta arrestin 2 mobilization. However, mutant receptor T98P exhibited constitutive beta arrestin recruitment, while mutant receptor I256A showed a CCL20-induced increase in mobilization.
520 $a To study interactions between CCR6 and CCL20, I applied a membrane tethered ligand (MTL) strategy that has been used by the Kopin laboratory to probe the importance of peptide domains and explore GPCR-ligand interactions. Generation and subsequent mutagenesis of tethered CCL20 highlighted the importance of the ligand N- and C-terminus of CCL20 in receptor activation.
520 $a An improved understanding of CCR6-related physiology and pathophysiology is needed for the design of safe and effective therapeutic interventions. In an effort to probe underlying molecular and pharmacological properties that influence CCR6 signaling, this thesis contributes in vitro tools to expedite CCR6 drug development and loss-of-function variants that deserve follow up as candidate etiologic factors in selected inflammatory diseases.
590 $a School code: 0845.
650 4 $a Pharmacology. $3 634543
650 4 $a Immunology. $3 611031
650 4 $a Molecular biology. $3 517296
690 $a 0419
690 $a 0982
690 $a 0307
710 2 $a Sackler School of Graduate Biomedical Sciences (Tufts University). $b Pharmacology and Experimental Therapeutics. $3 3289511
773 0 $t Dissertation Abstracts International $g 78-07B(E).
790 $a 0845
791 $a Ph.D.
792 $a 2017
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10254519