STRUCTURE/FUNCTION STUDIES OF LONG-CHAIN BASES
STRUCTURE/FUNCTION STUDIES OF LONG-CHAIN BASES
批准号:
3305788
负责人:
ALFRED Harrison MERRILL
金额:
$19.11万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1991
资助国家:
美国
项目状态:
已结题
起止时间:
1991-07-01 至 1995-06-30
关键词:
HeLa cells blood lipoprotein cell growth regulation chemical bond chemical chain length computer assisted sequence analysis conformation cytotoxicity enzyme inhibitors epidermal growth factor growth factor receptors high performance liquid chromatography lipid metabolism lipid structure membrane lipids micelles nuclear magnetic resonance spectroscopy protein tyrosine kinase protonation radioimmunoassay second messengers sphingosine stereoisomer tissue /cell culture
中文摘要
鞘氨醇和其他长链碱基对细胞生长有不同的影响,
功能 它们抑制蛋白激酶C,激活酪氨酸激酶
表皮生长因子受体的活性,并影响一些
其他调节系统在相对较低的浓度(微摩尔)。
这些影响,以及相关的可能性,长链碱基可能
作为另一类“脂质第二信使”,
对这些化合物是如何制造和转化的,以及
它们行为的结构要求。 过去几
多年来,我们开发了一种立体选择性合成鞘氨醇的方法,
结构相关的化合物,使我们能够进行这样的
分析。 到目前为止,我们已经做了二十多个类似物,
它们作为蛋白激酶C和代表性细胞的抑制剂的效力
被认为是通过这种酶介导的功能。 我们还
确定了这些化合物的一些相关物理性质
(e.g.,氨基的pKa,
鞘氨醇,鞘氨醇在膜之间快速移动的能力
但倾向于与带负电荷的脂质结合)。 在这份补助金中,
我们计划:1)进一步完善结构特征,
抑制蛋白激酶C、刺激细胞生长等
这些化合物的细胞效应; 2)获得更完整的图片,
鞘氨醇在膜中的物理状态(例如
质子化,这将通过C-13 NMR测定),并将这些
观察其细胞效应;和3)确定代谢
鞘氨醇和相关化合物的立体异构体的命运。 这些
调查将提供有关
神经鞘氨醇的生物化学和细胞生物学,并可以提供有价值的
工具和洞察长链基地作为细胞行为的调节剂。
英文摘要
Sphingosine and other long-chain bases have diverse effects on cell
function. They inhibit protein kinase C, activate the tyrosine kinase
activity of the epidermal growth factor receptor, and affect a number of
other regulatory systems at relatively low (micromolar) concentrations.
These effects, and the associated possibility that long-chain bases may
serve as another class of "lipid second messenger," has rekindled
interest in how these compounds are made and turned over, as well as in
the structural requirements for their behavior. Over the last several
years, we have developed a stereoselective synthesis for sphingosine and
structurally related compounds that will allow us to conduct such
analyses. Thus far, we have made over two dozen analogs and determined
their potency as inhibitors of protein kinase C and representative cell
functions thought to be mediated via this enzyme. We have also
identified some of the relevant physical properties of these compounds
(e.g., the pKa of the amino group, the critical micelle concentration of
sphingosine, the ability of sphingosine to move rapidly between membranes
but to tend to associate with negatively charged lipids). In this grant,
we plan to: 1) refine further the structural features that result in
inhibition of protein kinase C, stimulation of cell growth, and other
cellular effects of these compounds; 2) gain a more complete picture of
the physical state of sphingosine in membranes (such as the degree of
protonation, which will be determined by C-13 NMR), and to relate these
observations to their cellular effects; and 3) determine the metabolic
fate of the stereoisomers of sphingosine and related compounds. These
investigations will provide fundamental information about the
biochemistry and cell biology of sphingosine, and could provide valuable
tools and insight into long-chain bases as modulators of cell behavior.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
INVESTIGATION OF 1-DEOXYDIHYDROCERAMIDE BIOSYNTHESIS BY MAMMALIAN CELLS
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批准号:8365570
-
项目类别:
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资助金额:$1.54万
-
财政年份:2011
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
1-DEOXY-SPHINGOID BASE AND 1-DEOXYDIHYDROCER BIOSYNTHESIS IN MAMALS
-
批准号:8170944
-
项目类别:
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资助金额:$1.75万
-
财政年份:2010
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负责人:ALFRED Harrison MERRILL
-
依托单位:
Chemoprevention via modulation of autophagy by sphingolipids
-
批准号:7860733
-
项目类别:
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资助金额:$7.17万
-
财政年份:2009
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Chemoprevention via modulation of autophagy by sphingolipids
-
批准号:7590890
-
项目类别:
-
资助金额:$7.17万
-
财政年份:2009
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
CELL SURFACE GLYCOSPHINGOLIPIDS SSEA-3 AND SSEA-4
-
批准号:7722618
-
项目类别:
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资助金额:$0.94万
-
财政年份:2008
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
SPHINGOLIPID METABOLISM IN THE RETINA
-
批准号:7722638
-
项目类别:
-
资助金额:$0.38万
-
财政年份:2008
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
CHARACTERIZATION OF (GLYCO)SPHINGOLIPIDS IN (EMBRYONIC) MOUSE CELLS
-
批准号:7722614
-
项目类别:
-
资助金额:$17.86万
-
财政年份:2008
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of Mammalian Ceramide Synthases
-
批准号:8237460
-
项目类别:
-
资助金额:$33.02万
-
财政年份:2007
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负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of Mammalian Ceramide Synthases
-
批准号:8655162
-
项目类别:
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资助金额:$31.7万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of Mammalian Ceramide Synthases
-
批准号:8841741
-
项目类别:
-
资助金额:$31.7万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of mammalian ceramide synthases
-
批准号:7857929
-
项目类别:
-
资助金额:$28.23万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of mammalian ceramide synthases
-
批准号:7414590
-
项目类别:
-
资助金额:$28.51万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
CELL SURFACE GLYCOSPHINGOLIPIDS SSEA-3 AND SSEA-4
-
批准号:7602785
-
项目类别:
-
资助金额:$0.62万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of mammalian ceramide synthases
-
批准号:7616751
-
项目类别:
-
资助金额:$28.51万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of mammalian ceramide synthases
-
批准号:7258008
-
项目类别:
-
资助金额:$29.64万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
CHARACTERIZATION OF (GLYCO)SPHINGOLIPIDS IN (EMBRYONIC) MOUSE CELLS
-
批准号:7602779
-
项目类别:
-
资助金额:$11.73万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
SPHINGOLIPID METABOLISM IN THE RETINA
-
批准号:7602810
-
项目类别:
-
资助金额:$0.25万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
Characterization of Mammalian Ceramide Synthases
-
批准号:8452170
-
项目类别:
-
资助金额:$30.59万
-
财政年份:2007
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
CHARACTERIZATION OF (GLYCO)SPHINGOLIPIDS IN (EMBRYONIC) MOUSE CELLS
-
批准号:7359032
-
项目类别:
-
资助金额:$11.74万
-
财政年份:2006
-
负责人:ALFRED Harrison MERRILL
-
依托单位:
SPHINGOLIPID METABOLISM IN THE RETINA
-
批准号:7359083
-
项目类别:
-
资助金额:$0.62万
-
财政年份:2006
-
负责人:ALFRED Harrison MERRILL
-
依托单位: