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Molecular analysis of the role of Fc...

Joshi, Trupti Prabhakar.

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Molecular analysis of the role of FcgammaRIIb, ship and PI 3-kinase in macrophage Fcgamma receptor function.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Molecular analysis of the role of FcgammaRIIb, ship and PI 3-kinase in macrophage Fcgamma receptor function./
作者:	Joshi, Trupti Prabhakar.
面頁冊數:	165 p.
附註:	Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: 3765.
Contained By:	Dissertation Abstracts International68-06B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3268894
ISBN:	9780549073130

Molecular analysis of the role of FcgammaRIIb, ship and PI 3-kinase in macrophage Fcgamma receptor function.
Joshi, Trupti Prabhakar.

Molecular analysis of the role of FcgammaRIIb, ship and PI 3-kinase in macrophage Fcgamma receptor function. - 165 p.

Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: 3765.

Thesis (Ph.D.)--The Ohio State University, 2007.

Fcgamma Receptors expressed on macrophages are engaged and activated by immune-complexes and tumor cells opsonized with antibodies. This activation leads to elimination of immune-complexes via the process of phagocytosis and the destruction of antibody-coated tumor cells through a process called antibody-dependent cell-mediated cytotoxicity (ADCC). Both these events are accompanied by the release of inflammatory mediators. Although essential for the elimination of invading microbes or tumor cells, the release of inflammatory mediators needs to be regulated to prevent collateral tissue damage. FcgammaR-mediated responses are regulated by simultaneous engagement of activating and inhibitory Fcgamma receptors and by the activation of various kinases and phosphatases. In this study we have examined the molecular details of regulation of FcgammaR functions by the inhibitory FcgammaRIIb and the intracellular lipid phosphatases and lipid kinases. Specifically we have investigated the role of FcgammaRIIb, the inositol phosphatase SHIP-1 and phosphatidylinositol 3-kinase (PI 3-Kinase).

ISBN: 9780549073130Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Molecular analysis of the role of FcgammaRIIb, ship and PI 3-kinase in macrophage Fcgamma receptor function.
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100 1 $a Joshi, Trupti Prabhakar. $3 1924525
245 1 0 $a Molecular analysis of the role of FcgammaRIIb, ship and PI 3-kinase in macrophage Fcgamma receptor function.
300 $a 165 p.
500 $a Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: 3765.
500 $a Adviser: Susheela Tridandapani.
502 $a Thesis (Ph.D.)--The Ohio State University, 2007.
520 $a Fcgamma Receptors expressed on macrophages are engaged and activated by immune-complexes and tumor cells opsonized with antibodies. This activation leads to elimination of immune-complexes via the process of phagocytosis and the destruction of antibody-coated tumor cells through a process called antibody-dependent cell-mediated cytotoxicity (ADCC). Both these events are accompanied by the release of inflammatory mediators. Although essential for the elimination of invading microbes or tumor cells, the release of inflammatory mediators needs to be regulated to prevent collateral tissue damage. FcgammaR-mediated responses are regulated by simultaneous engagement of activating and inhibitory Fcgamma receptors and by the activation of various kinases and phosphatases. In this study we have examined the molecular details of regulation of FcgammaR functions by the inhibitory FcgammaRIIb and the intracellular lipid phosphatases and lipid kinases. Specifically we have investigated the role of FcgammaRIIb, the inositol phosphatase SHIP-1 and phosphatidylinositol 3-kinase (PI 3-Kinase).
520 $a In the first part of this dissertation, we tested the functional differences between the two isoforms of human FcgammaRIIb, b1 and b2, in macrophages. The results of these experiments revealed that both FcgammaRIIb1 and FcgammaRIIb2 are equivalently surface expressed, undergo tyrosine phosphorylation upon activation and induce the phosphorylation of SHIP-1. Both FcgammaRIIb1 and FcgammaRIIb2 downregulate phagocytosis and TNFalpha production to a similar extent. Together these findings demonstrate that hFcalphaRIIb1 and b2 are both functional inhibitory receptors in the phagocytic process.
520 $a In the second part, we examined the influence of inositol phosphatase SHIP-1 on phagocytosis-associated events and show for the first time that SHIP-1 negatively regulates FcgammaR-induced production of inflammatory cytokines IL-1beta and IL-6 as well as superoxide generation in macrophages. Analysis of the molecular mechanisms of regulation established that SHIP-1 regulates the activation of PI 3-kinase and Ras/Erk pathway upstream of IL-1beta and IL-6 production and the activation of Rac upstream of superoxide production. Interestingly, the modulation of the PI 3-kinase pathway by SHIP-1 is dependent on its catalytic activity whereas the regulation of the Ras/Erk pathway is independent of SHIP-1's catalytic activity.
520 $a In the last part of this dissertation, we investigated the molecular mechanisms involved in the process of macrophage-mediated ADCC. We show for the first time that activation of the PI 3-kinase/Akt pathway plays a critical role in macrophage-mediated ADCC against B cell lymphoma cells. Our results further show that in addition to the release of lytic mediators such as nitric oxide, the process of conjugate formation between macrophages and antibody-coated tumor cells is essential for cytolysis of tumor cells. We then demonstrate that the PI 3-kinase/Akt pathway regulates macrophage-mediated ADCC through its influence on cytoskeletal remodeling required for conjugate formation event.
520 $a Taken together these findings provide novel insights into the regulation of the phagocytic process by FcgammaRIIb and inositol phosphatase SHIP-1 and regulation of macrophage-mediated ADCC by the PI 3-kinase/Akt pathway.
590 $a School code: 0168.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Health Sciences, Immunology. $3 1017716
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790 1 0 $a Tridandapani, Susheela, $e advisor
790 $a 0168
791 $a Ph.D.
792 $a 2007
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