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The role and regulation of host hypo...

Menendez, Matthew Thomas.

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The role and regulation of host hypoxia inducible factor-1 in Toxoplasma gondii infection.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The role and regulation of host hypoxia inducible factor-1 in Toxoplasma gondii infection./
作者:	Menendez, Matthew Thomas.
面頁冊數:	219 p.
附註:	Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.
Contained By:	Dissertation Abstracts International76-10B(E).
標題:	Microbiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3692255
ISBN:	9781321820546

The role and regulation of host hypoxia inducible factor-1 in Toxoplasma gondii infection.
Menendez, Matthew Thomas.

The role and regulation of host hypoxia inducible factor-1 in Toxoplasma gondii infection. - 219 p.

Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.

Thesis (Ph.D.)--The University of Oklahoma Health Sciences Center, 2015.

Although it is established that oxygen availability regulates cellular metabolism and growth, little is known regarding how intracellular pathogens utilize host factors to grow at physiological oxygen levels. A large-scale human siRNA screen identified host Hexokinase 2 (HK2) as important for Toxoplasma gondii growth at physiological oxygen tensions. HK2 is a known hypoxiainducible transcription factor (HIF-1) target gene, which is important for Toxoplasma growth. Infection increases HK2 transcript and protein levels in a HIF-1-dependent manner. In addition, ectopic HK2 expression in HIF-1-deficient cells complements Toxoplasma growth at 3% oxygen. Lactate levels are increased in a HIF-1-dependent manner post-infection suggesting that enhanced HK2 expression in parasite-infected cells is functionally significant. Parasite dependence on host HK2 and HIF-1 expression is not restricted to transformed cell lines, as both are required for parasite growth in non-transformed C2C12 myoblasts and HK2 is upregulated in vivo following infection. Interestingly, HK2 dissociates from the outer mitochondrial membrane, which is important for parasite growth at 3% oxygen.

ISBN: 9781321820546Subjects--Topical Terms:

536250
Microbiology.

The role and regulation of host hypoxia inducible factor-1 in Toxoplasma gondii infection.
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245 1 4 $a The role and regulation of host hypoxia inducible factor-1 in Toxoplasma gondii infection.
300 $a 219 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.
500 $a Adviser: Jimmy Ballard.
502 $a Thesis (Ph.D.)--The University of Oklahoma Health Sciences Center, 2015.
520 $a Although it is established that oxygen availability regulates cellular metabolism and growth, little is known regarding how intracellular pathogens utilize host factors to grow at physiological oxygen levels. A large-scale human siRNA screen identified host Hexokinase 2 (HK2) as important for Toxoplasma gondii growth at physiological oxygen tensions. HK2 is a known hypoxiainducible transcription factor (HIF-1) target gene, which is important for Toxoplasma growth. Infection increases HK2 transcript and protein levels in a HIF-1-dependent manner. In addition, ectopic HK2 expression in HIF-1-deficient cells complements Toxoplasma growth at 3% oxygen. Lactate levels are increased in a HIF-1-dependent manner post-infection suggesting that enhanced HK2 expression in parasite-infected cells is functionally significant. Parasite dependence on host HK2 and HIF-1 expression is not restricted to transformed cell lines, as both are required for parasite growth in non-transformed C2C12 myoblasts and HK2 is upregulated in vivo following infection. Interestingly, HK2 dissociates from the outer mitochondrial membrane, which is important for parasite growth at 3% oxygen.
520 $a It is currently unknown how Toxoplasma promotes HIF-1 activation. Interestingly, the HIF-1 negative regulator prolyl-hydroxylase 2 (PHD2) is posttranslationally decreased post-infection in a lysosome-dependent manner. PHD2 proteolysis however was independent of bulk protein degradation as PHD2 was not stabilized in Atg5-depleted cells post-infection. Cytosolic proteins can be selectively targeted to the lysosome for proteolysis via chaperone-mediated autophagy (CMA) or endosomal microautophagy (e-MI) if they contain a consensus KFERQ-like motif, which is present in PHD2 (KFDRL). To test its relevance, the stability of truncated PHD2 mutants with and without the putative CMA motif (PHD2Delta29 and PHD2Delta71 respectively) were assessed in parasiteinfected cells. PHD2Delta29 levels were decreased similar to WT-PHD2, whereas PHD2Delta71 levels were stable post-infection suggesting that the putative CMA motif may regulate PHD2 levels post-infection. The functional significance of the KFDRL motif was assessed by expressing the PHD2K359A mutant in parasiteinfected cells followed by measuring HIF-1 activation. PHD2K359A attenuated HIF- 1 activation compared to infected cells expressing WT-PHD2. Lastly, cells increase CMA activity by increasing LAMP-2A abundance. LAMP-2A levels however were decreased by >75% following infection suggesting that PHD2 levels are regulated by a CMA-independent mechanism. Thus, future experiments will test the hypothesis that Toxoplasma regulates PHD2 levels via e-MI.
590 $a School code: 0361.
650 4 $a Microbiology. $3 536250
650 4 $a Parasitology. $3 635062
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