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Characterizing the role of Guanine E...

Zou, Siying.

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Characterizing the role of Guanine Exchange Factors in Megakaryopoiesis and Thrombopoiesis and Platelet Function.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Characterizing the role of Guanine Exchange Factors in Megakaryopoiesis and Thrombopoiesis and Platelet Function./
Author:	Zou, Siying.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
Description:	150 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-01(E), Section: B.
Contained By:	Dissertation Abstracts International78-01B(E).
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10160844
ISBN:	9781369157390

Characterizing the role of Guanine Exchange Factors in Megakaryopoiesis and Thrombopoiesis and Platelet Function.
Zou, Siying.

Characterizing the role of Guanine Exchange Factors in Megakaryopoiesis and Thrombopoiesis and Platelet Function. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 150 p.

Source: Dissertation Abstracts International, Volume: 78-01(E), Section: B.

Thesis (Ph.D.)--Yale University, 2016.

This item is not available from ProQuest Dissertations & Theses.

Megakaryopoiesis, the process by which hematopoietic stem cells develop into mature megakaryocytes (MK), along with thrombopoiesis, the process of platelet production/release, and platelet function are critical processes for maintaining hemostasis. Although some of the key regulators have been identified, much remains to be uncovered regarding how these processes are regulated and how signals from different pathways are integrated.

ISBN: 9781369157390Subjects--Topical Terms:

3172791
Cellular biology.

Characterizing the role of Guanine Exchange Factors in Megakaryopoiesis and Thrombopoiesis and Platelet Function.
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100 1 $a Zou, Siying. $3 3285951
245 1 0 $a Characterizing the role of Guanine Exchange Factors in Megakaryopoiesis and Thrombopoiesis and Platelet Function.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2016
300 $a 150 p.
500 $a Source: Dissertation Abstracts International, Volume: 78-01(E), Section: B.
500 $a Adviser: Diane S. Krause.
502 $a Thesis (Ph.D.)--Yale University, 2016.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a Megakaryopoiesis, the process by which hematopoietic stem cells develop into mature megakaryocytes (MK), along with thrombopoiesis, the process of platelet production/release, and platelet function are critical processes for maintaining hemostasis. Although some of the key regulators have been identified, much remains to be uncovered regarding how these processes are regulated and how signals from different pathways are integrated.
520 $a Guanine exchange factors (GEF) are a group of proteins that are capable of mediating the exchange of guanosine diphosphate (GDP) to guanosine triphosphate (GTP) of Rho proteins, therefore to promote the activities of Rho. Mammalian cells express over 80 different guanine exchange factors, which regulate multiple cellular processes in spatial- and temporal-specific manners. This study investigates the roles of two GEFs, Rho Guanine Nucleotide Exchange Factor 3 (ARHGEF3) and Leukemia Associated RhoGEF (LARG), in megakaryopoiesis, thrombopoiesis and platelet function.
520 $a Rho Guanine Nucleotide Exchange Factor 3 (ARHGEF3) is a less well-characterized GEF, with limited studies about its function and signaling pathways. Several recent genome-wide association studies identified a strong association between the occurrence of a single nucleotide polymorphism (SNP; rs1354034) within an intron of the longest isoform of the ARHGEF3 gene, and both decreased platelet count and increased mean platelet volume (MPV). The inverse relationship between platelet count and MPV suggests that the regulation of ARHGEF3 may influence megakaryocytes and platelets. In addition, knocking down of Arhgef3 in zebrafish abrogates the formation of fish thrombocytes (platelets). Here, we tested the hypothesis that ARHGEF3 has a role in megakaryopoiesis and thrombopoiesis. First, we created a knockout (KO) mouse model of Arhgef3. We found that Arhgef3 KO mice have enlarged platelets and a slight delay in platelet recovery when challenged with antibody-induced thrombocytopenia. However, no obvious defects in megakaryocytes or platelets function were observed in the KO mice. When we further examined the ARHGEF3 gene and its associated SNP rs1354034 in human cells, we found that ARHGEF3 exhibits a stronger phenotypic effect, suggesting perhaps a more significant role in the human system. rs1354034 is located in what is likely the promoter, of the most commonly expressed isoform of ARHGEF3 in human megakaryocytes, and is an expression quantitative trait locus (eQTL) that correlates strongly with the ARHGEF3 expression level in human platelets. In addition, the SNP resides in a DNase I hypersensitive region in human megakaryocyte nucleus, potentially regulating the binding of several nuclear proteins to DNA. Lastly, rs1354034 is strongly associated with human platelet function. These data show that while ARHGEF3 displays a weaker effect for murine megakaryocytes and platelets, it plays a much more prominent role in the human system.
520 $a The mild phenotype of the Arhgef3 KO mice drove us to look for other GEF proteins that may have a more prominent role in MKs and/or platelets. Leukemia Associated RhoGEF (LARG) is an interesting candidate as it is the most highly expressed GEF in human platelets. We found that knocking down LARG alone inhibits human, but not murine, megakaryocyte development. Further characterization of a global Larg KO mouse model showed that while the KO mice have normal megakaryopoiesis, they exhibit platelet defects including macrothrombocytopenia, internal bleeding in the ovaries and prolonged bleeding times. In addition, we observed that Larg KO platelets have impaired aggregation, alpha-granule release and integrin alpha2bbeta3 activation specifically in response to thrombin and thromboxane, but not to adenosine diphosphate (ADP). The same agonist-specific reduction in platelet aggregation occurs in human platelets when treated with a LARG inhibitor. These defects are accompanied by reduced RhoA activation and myosin light chain phosphorylation. Thrombin and thromboxane are well characterized platelet agonists that stimulate their respective receptors coupled with Galpha13, indicating that. LARG is an important signal transducer between Galpha13-coupled receptors and RhoA. Lastly, Larg KO mice are protected from in vivo thrombus formation. Together, these results establish that LARG plays an essential role in human MK development but has a less important role for mucine MKs. LARG is an important regulator of platelet function in both human and mice and can serve as a potential anti-platelet drug target. The findings presented here contribute to further understanding of the mechanisms of megakaryopoiesis, thrombopoiesis and platelet function.
520 $a The different roles of a same protein in the human versus the mouse system suggest inherent differences between species, despite both systems originating from the mammalian clade. Our study advocates for more species awareness in related research, and it is more desirable for studies on both species to be conducted in parallel.
590 $a School code: 0265.
650 4 $a Cellular biology. $3 3172791
690 $a 0379
710 2 $a Yale University. $3 515640
773 0 $t Dissertation Abstracts International $g 78-01B(E).
790 $a 0265
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10160844