LARGE NEUTRAL AMINO ACIDS--TRANSPORT AND EFFECTS ON OXIDATIVE BRAIN METABOLISM
大分子中性氨基酸——转运及其对脑氧化代谢的影响
基本信息
- 批准号:6108369
- 负责人:
- 金额:$ 17.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-05-01 至 2000-04-30
- 项目状态:已结题
- 来源:
- 关键词:aerobiosis aminoacid transport astrocytes bioenergetics brain metabolism branched chain aminoacid catecholamines cerebellum corpus striatum enzyme activity gamma aminobutyrate glutamate dehydrogenase glutamates glutamine granule cell human tissue intracellular transport ketoacid laboratory rat membrane transport proteins microdialysis neurons nitrogen metabolism serotonin tissue /cell culture
项目摘要
We hypothesize that elevated levels of branched chain amino acids (BCAA)
and their alpha-keto acids (BCKA) perturb not only amino acid transport,
but also affect brain energy metabolism, disrupt the equilibrium of
intercellular trafficking, and alter flux through enzymes involved in
amino acid neurotransmitter synthesis. Ultimately such perturbations may
have profound effects on neurodevelopment leading to mental retardation.
Four recent findings from our laboratory support this hypothesis: 1)
elevated levels of alpha-ketoisocaproate (alpha-KIC) introduced via
microdialysis stimulate the in vivo oxidation of glutamate and glutamine,
altering the energy states of the cells and decreasing the availability of
glutamate for neurotransmitter function; 2) we have demonstrated in the
intact brain that the oxidative metabolism of glutamate and glutamine is
compartmentalized with glutamine oxidation rates in the hippocampus being
approximately 5-fold greater than glutamate oxidation rates; 3) elevated
levels of leucine and alpha-KIC, introduced via microdialysis to the
interstitial space of rat brain, result in a 2-4 fold increase in the
interstitial concentrations of large neutral amino acids (LNAA) and
glutamine and 4) cultured rat cortical neurons and astrocytes have a
pronounced different intracellular response to exogenous BCAA and BCKA.
The proposed studies will: 1) combine two established methodologies, i.e.,
microdialysis and specific cellular ablation, to determine the effect of
BCAA and BCKA on the oxidative metabolism by specific cell types in
different brain regions; 2) determine the effect of BCAA and BCKA on amino
acid exchanges into the interstitial fluid following ablation of specific
types of brain cells by neurotoxic compounds; 3) characterize transport of
LNAA by neuronal cells; 4) characterize the effect of LNAA and BCKA on
glutamate/glutamine metabolism in the intact rat brain and in culture
brain cells of know cell type. Inclusion of human astrocytes, normal and
trisomic 21, should provide valuable information about the etiology of
mental retardation resulting from in born errors of metabolism and
chromosomal abnormalities and will provide guidelines for clinical
approaches to these conditions.
我们假设支链氨基酸(BCAA)水平升高
并且它们的α-酮酸(BCKA)不仅干扰氨基酸转运,
还会影响大脑的能量代谢,
细胞间运输,并改变通过参与酶通量
氨基酸神经递质合成最终,这种扰动可能
对神经发育有深远的影响,导致智力迟钝。
我们实验室最近的四项发现支持了这一假设:
α-酮异己酸(α-KIC)水平升高,
微透析刺激谷氨酸和谷氨酰胺的体内氧化,
改变细胞的能量状态并降低细胞的可用性,
谷氨酸的神经递质功能; 2)我们已经证明,
完整的大脑,谷氨酸和谷氨酰胺的氧化代谢是
海马区谷氨酰胺氧化率被划分为
比谷氨酸氧化速率高约5倍; 3)升高
水平的亮氨酸和α-KIC,通过微透析引入到
大鼠脑的间隙,导致2-4倍的增加,
大分子中性氨基酸(LNAA)的间隙浓度,
谷氨酰胺和4)培养的大鼠皮层神经元和星形胶质细胞具有
对外源性BCAA和BCKA的细胞内反应明显不同。
拟议的研究将:1)结合联合收割机两种既定方法,即,
微透析和特异性细胞消融,以确定
BCAA和BCKA对特定细胞类型氧化代谢的影响
2)确定BCAA和BCKA对氨基的影响
酸交换进入组织间液后,消融特定的
神经毒性化合物对脑细胞类型的影响; 3)表征
4)表征LNAA和BCKA对神经元细胞的作用,
完整大鼠脑和培养物中的谷氨酸/谷氨酰胺代谢
已知细胞类型的脑细胞。包括人星形胶质细胞,正常和
三体21,应该提供有关病因学的有价值的信息,
先天性代谢缺陷导致的智力迟钝,
染色体异常,并将为临床
接近这些条件。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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H. Ronald Zielke其他文献
Effect of α-Ketoisocaproate and Leucine on the in Vivo Oxidation of Glutamate and Glutamine in the Rat Brain
- DOI:
10.1023/a:1027325620983 - 发表时间:
1997-09-01 - 期刊:
- 影响因子:3.800
- 作者:
H. Ronald Zielke;Yinyin Huang;Peter J. Baab;Roger M. Collins;Carol L. Zielke;J. Tyson Tildon - 通讯作者:
J. Tyson Tildon
Reciprocal regulation of glucose and glutamine utilization by cultured human diploid fibroblasts
培养的人二倍体成纤维细胞对葡萄糖和谷氨酰胺利用的相互调节
- DOI:
- 发表时间:
1978 - 期刊:
- 影响因子:5.6
- 作者:
H. Ronald Zielke;P. Ozand;J. Tyson Tildon;D. Sevdalian;M. Cornblath - 通讯作者:
M. Cornblath
Effect of fluorocitrate on cerebral oxidation of lactate and glucose in freely moving rats
氟柠檬酸盐对自由活动大鼠脑乳酸和葡萄糖氧化的影响
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:4.7
- 作者:
H. Ronald Zielke;C. Zielke;P. Baab;J. Tyson Tildon - 通讯作者:
J. Tyson Tildon
Sudden unexpected death due to inflammatory myofibroblastic tumor of the heart: a case report and review of the literature
- DOI:
10.1007/s00414-010-0496-7 - 发表时间:
2010-07-31 - 期刊:
- 影响因子:2.300
- 作者:
Ling Li;Allen Burke;Jie He;Lin Chang;H. Ronald Zielke;David R. Fowler - 通讯作者:
David R. Fowler
H. Ronald Zielke的其他文献
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{{ truncateString('H. Ronald Zielke', 18)}}的其他基金
Mechanisms for Extracellular Glutamate Formation in Brai
Brai 细胞外谷氨酸形成机制
- 批准号:
7013462 - 财政年份:2004
- 资助金额:
$ 17.82万 - 项目类别:
LARGE NEUTRAL AMINO ACIDS--TRANSPORT AND EFFECTS ON OXIDATIVE BRAIN METABOLISM
大分子中性氨基酸——转运及其对脑氧化代谢的影响
- 批准号:
6301883 - 财政年份:2000
- 资助金额:
$ 17.82万 - 项目类别:
LARGE NEUTRAL AMINO ACIDS--TRANSPORT AND EFFECTS ON OXIDATIVE BRAIN METABOLISM
大分子中性氨基酸——转运及其对脑氧化代谢的影响
- 批准号:
6272053 - 财政年份:1998
- 资助金额:
$ 17.82万 - 项目类别:
GLUTAMINE, GLUTAMATE, BRANCHED CHAIN AMINO ACIDS AND OXIDATIVE BRAIN METABOLISM
谷氨酰胺、谷氨酸盐、支链氨基酸和氧化脑代谢
- 批准号:
6240923 - 财政年份:1997
- 资助金额:
$ 17.82万 - 项目类别:
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