CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
基本信息
- 批准号:6789383
- 负责人:
- 金额:$ 33.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-09-01 至 2006-08-31
- 项目状态:已结题
- 来源:
- 关键词:AIDSanemiacachexiacell lineceramidescomorbiditycytokinegrowth factor receptorshormone receptorhormone regulation /control mechanisminsulin receptorinsulinlike growth factorinterleukin 1molecular pathologymyeloid stem cellmyoblastsmyotubesneutropeniaphosphatidylinositol 3 kinaseprotein biosynthesisprotein kinasesarcopeniaserine proteinasestranscription factortyrosine
项目摘要
DESCRIPTION (provided by applicant): The anemia, neutropenia, loss of lean body
mass and mortality of AIDS patients with wasting are associated with elevated
levels of the proinflammatory cytokines TNFalpha and IL-1beta. AIDS patients with
wasting are often given a 12- week therapy with very high doses of recombinant
human growth hormone to increase plasma IGF-I, lean muscle mass and quality of
life. However, the responsiveness of both hematopoietic and muscle cells to
IGF-I has been documented to be defective in these patients. The central
hypothesis of this application is that TNFalpha and IL-lbeta are responsible for
inducing a state of IGF-I receptor resistance, which contributes to not only
muscle wasting but also to the anemia and neutropenia of AIDS. IGF-I targets
both hematopoietic myeloid progenitor cells and muscle myoblasts, and here we
hypothesize that the molecular mechanism for IGF-I receptor resistance in
wasting AIDS patients is caused by proinflammatory cytokines. Objective 1 will
test the idea that IGF-I promotes promyeloid cell survival by blocking
activation of the caspase family of serine proteases and whether this is
inhibited by TNFa. Objective 2 focuses on the survival promoting activity of
the tyrosine phosphorylated IGF-I receptor, including insulin-receptor
substrate- 1 (IRS-1), IRS-2, PI 3-kinase and Akt. Objective 3 will determine if
proinflammatory cytokines inhibit key IGF-I proliferative signals, including
Shc, EFK1/2, AFX forkhead transcription factors and the cyclin-dependent kinase
inhibitor 27. Finally, objective 4 will extend these results with myeloid
progenitor cells to muscle myoblasts. Preliminary results indicate that low
blood concentrations of TNFalpha and IL-1beta found in wasting AIDS patients inhibit
the ability of IGF-I to promote both protein synthesis and differentiation into
myotubes. This objective will also test the new idea that ceramide, a mediator
of the actions of both TNFalpha and IL-1beta, induces resistance of the IGF-I receptor
in muscle myoblasts. These studies are needed to understand how
clinically-relevant concentrations of proinflammatory cytokines in wasting AIDS
patients impair the functional ability of a major hormone receptor on both
immune and muscle myoblast cells.
描述(由申请人提供):贫血、中性粒细胞减少、瘦体质丧失
艾滋病患者消瘦的质量和死亡率均与升高
促炎细胞因子TNF α和IL-1 β的水平。艾滋病患者
通常给予12周的高剂量重组
人生长激素增加血浆IGF-I,瘦肌肉质量和质量
生活然而,造血细胞和肌肉细胞对
IGF-I已被证明在这些患者中存在缺陷。中央
本申请假设是TNF α和IL-1 β负责
诱导IGF-I受体抗性的状态,这不仅有助于
肌肉萎缩,而且还导致艾滋病的贫血和中性粒细胞减少。IGF-I靶点
造血骨髓祖细胞和肌肉成肌细胞,在这里,我们
假设IGF-I受体抵抗的分子机制是
艾滋病患者的消瘦是由促炎细胞因子引起的。目标1将
测试IGF-I通过阻断
丝氨酸蛋白酶的半胱天冬酶家族的激活,以及这是否是
受到TNFa的抑制。目标2关注的是
酪氨酸磷酸化IGF-I受体,包括胰岛素受体
底物-1(IRS-1)、IRS-2、PI 3-激酶和Akt。目标3将确定
促炎细胞因子抑制关键的IGF-I增殖信号,包括
Shc、EFK 1/2、AFX叉头转录因子和细胞周期蛋白依赖性激酶
抑制剂27.最后,目标4将扩展这些结果与骨髓
祖细胞转化为成肌细胞。初步结果显示,低
在消瘦的艾滋病患者中发现的TNF α和IL-1 β的血液浓度抑制了
IGF-I促进蛋白质合成和分化为
肌管这一目标也将测试新的想法,神经酰胺,一个调解人
TNF α和IL-1 β的作用,诱导IGF-I受体的抵抗,
在肌肉成肌细胞中。需要这些研究来了解
消耗性艾滋病患者促炎细胞因子的临床相关浓度
患者损害了两个细胞上主要激素受体的功能能力,
免疫和肌肉成肌细胞。
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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Keith W Kelley其他文献
Keith W Kelley的其他文献
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{{ truncateString('Keith W Kelley', 18)}}的其他基金
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7588876 - 财政年份:2007
- 资助金额:
$ 33.88万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7986896 - 财政年份:2007
- 资助金额:
$ 33.88万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
8049171 - 财政年份:2007
- 资助金额:
$ 33.88万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7795124 - 财政年份:2007
- 资助金额:
$ 33.88万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7174006 - 财政年份:2007
- 资助金额:
$ 33.88万 - 项目类别:
Neuroimmune Mechanisms of Depressive-Like Behavior During Aging
衰老过程中抑郁样行为的神经免疫机制
- 批准号:
7391645 - 财政年份:2007
- 资助金额:
$ 33.88万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6604731 - 财政年份:2002
- 资助金额:
$ 33.88万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6930551 - 财政年份:2002
- 资助金额:
$ 33.88万 - 项目类别:
CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS
艾滋病合并症中细胞因子和激素的相互作用
- 批准号:
6495926 - 财政年份:2002
- 资助金额:
$ 33.88万 - 项目类别:
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