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Substrate phosphorylation of beta-ad...

Ruse, Cristian Ion.

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Substrate phosphorylation of beta-adrenergic pathway in failing and non-failing human hearts: Identification and quantitation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Substrate phosphorylation of beta-adrenergic pathway in failing and non-failing human hearts: Identification and quantitation./
作者:	Ruse, Cristian Ion.
面頁冊數:	144 p.
附註:	Source: Dissertation Abstracts International, Volume: 65-01, Section: B, page: 0118.
Contained By:	Dissertation Abstracts International65-01B.
標題:	Biophysics, General. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3118914

Substrate phosphorylation of beta-adrenergic pathway in failing and non-failing human hearts: Identification and quantitation.
Ruse, Cristian Ion.

Substrate phosphorylation of beta-adrenergic pathway in failing and non-failing human hearts: Identification and quantitation. - 144 p.

Source: Dissertation Abstracts International, Volume: 65-01, Section: B, page: 0118.

Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 2004.

Decreased cardiac contractility is a hallmark of human heart failure. Myofilament proteins can be viewed as foci of signals that modulate the transition from hypertrophy and failure. Multiple phosphorylation sites mutually regulate each other in state of modification, either in response to down-regulated beta-adrenergic pathway or growth signals. However, in most of the cases the phosphorylation state of these substrates has been investigated only at the single protein level. Rarely, the differences in site-specific phosphorylation states of these substrates in normal and diseased states have been quantified, either in relative or absolute units. One of the aims of this study is to analyze the phosphorylation, by site-specific mapping and quantification, of cardiac TnI. Cardiac TnI is essential for inhibiting the muscle contraction in the absence of Ca2+ and is the site of phosphorylation from multiple signaling pathways. Also, we addressed the issue of simultaneous analysis of multiple phosphorylation sites on multiple substrates in the human heart.Subjects--Topical Terms:

1019105
Biophysics, General.

Substrate phosphorylation of beta-adrenergic pathway in failing and non-failing human hearts: Identification and quantitation.
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245 1 0 $a Substrate phosphorylation of beta-adrenergic pathway in failing and non-failing human hearts: Identification and quantitation.
300 $a 144 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-01, Section: B, page: 0118.
500 $a Adviser: Meredith Bond.
502 $a Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 2004.
520 $a Decreased cardiac contractility is a hallmark of human heart failure. Myofilament proteins can be viewed as foci of signals that modulate the transition from hypertrophy and failure. Multiple phosphorylation sites mutually regulate each other in state of modification, either in response to down-regulated beta-adrenergic pathway or growth signals. However, in most of the cases the phosphorylation state of these substrates has been investigated only at the single protein level. Rarely, the differences in site-specific phosphorylation states of these substrates in normal and diseased states have been quantified, either in relative or absolute units. One of the aims of this study is to analyze the phosphorylation, by site-specific mapping and quantification, of cardiac TnI. Cardiac TnI is essential for inhibiting the muscle contraction in the absence of Ca2+ and is the site of phosphorylation from multiple signaling pathways. Also, we addressed the issue of simultaneous analysis of multiple phosphorylation sites on multiple substrates in the human heart.
520 $a We developed a new methodology for quantitative dynamics of site-specific protein phosphorylation using mass spectrometry. Based on the properties of one the digested peptides of cardiac TnI, we introduced the concept of native reference peptide. We provided proof of principle by obtaining absolute quantification of site-specific phosphorylation at Ser44 of cardiac TnI by PKCbetaII.
520 $a The second part of this study concerns the simultaneous analysis of multiple phosphorylation substrates at the level of an individual phosphorylation site. We used chromatography and mass spectrometry for identification of peptides generated by in solution digestion of all of the cardiac proteins. We propose an integrated infrastructure for large-scale analysis of cardiac gene products: mRNA, proteins and phosphoproteins. We were able to follow the fate of 447 gene products from nonfailing human heart. Approximately 50 phosphoproteins were detected and a number of site-specific phosphorylations including several known substrates of the beta-adrenergic pathway (phospholamban, cardiac TnI and myosin-binding protein C) as well as new phosphoproteins were identified. Future studies will expand the knowledge and unify the identification and quantification of site-specific phosphorylation for large-scale analysis of cardiac substrates both in normal and pathophysiological states.
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