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RAS pathway activation in the develo...

Wiesner, Stephen Michael.

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RAS pathway activation in the development of myeloproliferative disorders and acute myeloid leukemia.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	RAS pathway activation in the development of myeloproliferative disorders and acute myeloid leukemia./
作者:	Wiesner, Stephen Michael.
面頁冊數:	130 p.
附註:	Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4614.
Contained By:	Dissertation Abstracts International66-09B.
標題:	Biology, Genetics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3188605
ISBN:	0542310678

RAS pathway activation in the development of myeloproliferative disorders and acute myeloid leukemia.
Wiesner, Stephen Michael.

RAS pathway activation in the development of myeloproliferative disorders and acute myeloid leukemia. - 130 p.

Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4614.

Thesis (Ph.D.)--University of Minnesota, 2005.

Three main sections are presented in this thesis. First is an investigation of genetic interaction between Stat5 and Nf1 in the development of MPD. Combinations of different knock out and conditional alleles are used in combination with inducible recombination in an attempt to address potential interactions. Currently, the role of STAT5 activation in MPD after NF1 gene loss is poorly understood, though previous studies have investigated the role of upstream signaling components in JMML without addressing STAT5 specifically. Data presented supports the hypothesis that Jak-Stat5 signaling plays a role in the development of MPD driven by Nf1 gene loss.

ISBN: 0542310678Subjects--Topical Terms:

1017730
Biology, Genetics.

RAS pathway activation in the development of myeloproliferative disorders and acute myeloid leukemia.
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245 1 0 $a RAS pathway activation in the development of myeloproliferative disorders and acute myeloid leukemia.
300 $a 130 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4614.
500 $a Adviser: David Andrew Largaespada.
502 $a Thesis (Ph.D.)--University of Minnesota, 2005.
520 $a Three main sections are presented in this thesis. First is an investigation of genetic interaction between Stat5 and Nf1 in the development of MPD. Combinations of different knock out and conditional alleles are used in combination with inducible recombination in an attempt to address potential interactions. Currently, the role of STAT5 activation in MPD after NF1 gene loss is poorly understood, though previous studies have investigated the role of upstream signaling components in JMML without addressing STAT5 specifically. Data presented supports the hypothesis that Jak-Stat5 signaling plays a role in the development of MPD driven by Nf1 gene loss.
520 $a Second, experiments were performed to determine what contribution loss of p19Arf makes to the development of MPD associated with Nf1 gene loss. Decreased or absent expression of p19Arf is a common occurrence in human malignant peripheral nerve sheath tumors associated with NF1 gene loss. However, the relationship between Nf1 and p19Arf in the hematopoietic system has not been addressed. These studies result in a varied disease phenotype and accelerated development of hematopoietic disease in compound knock-out mice.
520 $a Third, though mutated NRAS is found in JMML, occurs in variety of human AML, and is associated with progression of MDS to AML, the specific contribution activated NRAS makes to these diseases is uncertain. As no model of mutant NRAS existed at the outset of this work, a transgenic model of conditionally expressed oncogenic NRAS was created. Mice conditionally expressing oncogenic NRAS uniformly develop a chronic myeloproliferative disease that is repressed upon transgene repression. Hopefully, this model will serve as a useful tool in the study of diseases that are associated with activation NRAS mutations.
520 $a The studies presented here model hematopoietic changes that are known to be caused by RAS pathway activation existing as the primary genetic lesion. Studies of JMML suggest that the initiating mutation in hematopoietic disease not only contributes directly to the phenotype of the subsequent disease, but defines or restricts the spectrum of mutations that can contribute to the progression of disease, in essence making that cell permissive for discrete secondary genetic events. Furthermore, specific mutations are likely able to affect a limited spectrum of cells by limiting the cell type tropism of secondary events, the stage of cellular differentiation at which they occur, or both. By this logic, the three common primary genetic lesions in JMML are able to contribute to the development of this MDS/MPD by causing lineage and differentiation stage specific alterations in the physiology of the target cell that ultimately culminate in a specific disease phenotype. The restricted mutational pathway from the primary genetic lesion to overt JMML clearly is not a high frequency series of events, as JMML is an exceedingly rare disease, even among predisposed individuals. However, this rarity, combined with the consistent, well defined phenotype of the disease further supports the hypothesis of limited cell type permissiveness and restricted mutational progression.
590 $a School code: 0130.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Molecular. $3 1017719
690 $a 0369
690 $a 0307
710 2 0 $a University of Minnesota. $3 676231
773 0 $t Dissertation Abstracts International $g 66-09B.
790 1 0 $a Largaespada, David Andrew, $e advisor
790 $a 0130
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3188605