ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY
ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY
批准号:
6514214
负责人:
Martin Hauer-Jensen
金额:
$27.14万
依托单位国家:
美国
项目类别:
财政年份:
2000
资助国家:
美国
项目状态:
已结题
起止时间:
2000-07-01 至 2005-06-30
中文摘要
肠道辐射毒性(放射性肠病)是
以肠壁进行性纤维化和
炎性和纤维化细胞因子的过度表达,尤其是
转化生长因子β1(TGF-β1)。微血管损伤被认为是
在慢性放射性肠病的发病机制中具有重要作用。然而,
血管内皮细胞损伤、血管硬化症和
延迟性辐射毒性在体内尚未确定。临床
来自PI实验室的实验研究表明,
照射后肠道中血栓调节蛋白的下调。TM是一种内皮细胞
通过调节凝血酶起“天然抗凝剂”作用的细胞糖蛋白
功能。凝血酶除了在凝血中起关键作用外,还是一种重要的
炎症和组织重塑的调节剂。这些函数中有许多是
通过蛋白酶激活的受体(PAR)介导,最著名的是PAR-1,它
在实验性放射性肠病中表达上调。照射后,
TM水平不足可促进纤维蛋白沉积和上调转化生长因子-β1。
因此,纤维化刺激可能由转化生长因子-β1与
凝血酶的促凝血、促炎和促有丝分裂作用
通过标准杆1。这项拟议的研究考察了以下因素的相对重要性
这些过程在放射性肠病的发病机制中起重要作用。使用在体大鼠
和老鼠模型以及定量分子方法,该项目将
系统研究TM、PAR-1和转化生长因子-β的作用和相互关系
1.该项目将1)评估
内皮细胞TM、PAR-1、转化生长因子-β1与肠道结构性辐射
损伤,2)使用突变和基因敲除动物模型来检查特定的
结肠癌中TM、PAR-1和TGF-β1的相互关系及相对意义
放射性肠病,以及3)检测是否有特定的血小板抑制物
聚集和凝血酶将破坏结构、细胞和分子。
辐射引起的变化。这些实验将提供重要的新的
慢性疾病分子发病机制的研究进展
放射性肠病。全面了解这些潜在的
机制可以确定临床上相关的干预靶点和
促进制定治疗和预防战略,以尽量减少
肠道辐射毒性。
英文摘要
Intestinal radiation toxicity (radiation enteropathy) is
characterized by progressive fibrosis of the intestinal wall and
over-expression of inflammatory and fibrogenic cytokines, particularly
transforming growth factor b 1 (TGF-b 1). Microvascular injury is believed to
be important in the mechanisms of chronic radiation enteropathy. However,
direct molecular links among endothelial injury, vascular sclerosis, and
delayed radiation toxicity have not been established in vivo. Clinical
experimental studies from the PI's laboratory have shown a striking
down-regulation of thrombomodulin in irradiated intestine. TM is an endothelial
cell glycoprotein that acts as a "natural anticoagulant" by regulating thrombin
function. Thrombin, in addition to its key role in coagulation, is an important
regulator of inflammation and tissue remodeling. Many of these functions are
mediated through protease activated receptors (PAR), most notably PAR-1, which
is upregulated in experimental radiation enteropathy. After irradiation,
deficient levels of TM enhance fibrin deposition and upregulate TGF-b 1. The
fibrotic stimulus may thus be sustained by TGF-b 1 in concert with
procoagulant, pro-inflammatory, and mitogenic effects of thrombin, mediated
through PAR-1. The proposed research examines the relative significance of
these processes in the mechanisms of radiation enteropathy. Using in vivo rat
and mouse models along with quantitative molecular methods, the project will
systematically examine the roles and interrelationships of TM, PAR-1, and TGF-b
1. The project will 1) assess temporal and spatial associations among
endothelial cell TM, PAR-1, TGF- b 1, and structural intestinal radiation
injury, 2) use mutant and knockout animal models to examine specific
interrelationships and the relative significance of TM, PAR-1, and TGF-b 1 in
radiation enteropathy, and 3) test whether specific inhibitors of platelet
aggregation and thrombin will abrogate the structural, cellular, and molecular
changes induced by radiation. These experiments will provide significant new
information regarding the molecular pathogenesis and mechanisms of chronicity
of radiation enteropathy. A comprehensive understanding of these underlying
mechanisms may identify clinically relevant targets for intervention and
facilitate development of therapeutic and prophylactic strategies to minimize
intestinal radiation toxicity.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
2015 Annual Meeting of the Radiation Research Society
-
批准号:8889919
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项目类别:
-
资助金额:$1.0万
-
财政年份:2015
-
负责人:Martin Hauer-Jensen
-
依托单位:
Center for Studies of Host Response to Cancer Therapy
-
批准号:9095900
-
项目类别:
-
资助金额:$211.63万
-
财政年份:2015
-
负责人:Martin Hauer-Jensen
-
依托单位:
Center for Studies of Host Response to Cancer Therapy
-
批准号:9249611
-
项目类别:
-
资助金额:$211.63万
-
财政年份:2015
-
负责人:Martin Hauer-Jensen
-
依托单位:
Center for Studies of Host Response to Cancer Therapy
-
批准号:8811544
-
项目类别:
-
资助金额:$211.63万
-
财政年份:2015
-
负责人:Martin Hauer-Jensen
-
依托单位:
Somatostatin Analogs as Countermeasures against Intestinal Radiation Toxicity
-
批准号:8013117
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项目类别:
-
资助金额:$33.52万
-
财政年份:2010
-
负责人:Martin Hauer-Jensen
-
依托单位:
Somatostatin analogues as countermeasures against intestinal radiation toxicity
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批准号:7052919
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项目类别:
-
资助金额:$28.62万
-
财政年份:2005
-
负责人:Martin Hauer-Jensen
-
依托单位:
Endothelial Dysfunction in Intestinal Radiation Toxicity
-
批准号:7414609
-
项目类别:
-
资助金额:$28.61万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY
-
批准号:6633533
-
项目类别:
-
资助金额:$27.95万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
Endothelial Dysfunction in Intestinal Radiation Toxicity
-
批准号:7225494
-
项目类别:
-
资助金额:$28.61万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
Endothelial Dysfunction in Intestinal Radiation Toxicity
-
批准号:7610995
-
项目类别:
-
资助金额:$28.61万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY
-
批准号:6745581
-
项目类别:
-
资助金额:$28.79万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
Endothelial Dysfunction in Intestinal Radiation Toxicity
-
批准号:6973226
-
项目类别:
-
资助金额:$30.18万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY
-
批准号:6026907
-
项目类别:
-
资助金额:$27.62万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY
-
批准号:6377548
-
项目类别:
-
资助金额:$26.35万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
Endothelial Dysfunction in Intestinal Radiation Toxicity
-
批准号:7069653
-
项目类别:
-
资助金额:$29.47万
-
财政年份:2000
-
负责人:Martin Hauer-Jensen
-
依托单位:
Molecular Pathogenesis of Radiation Enteropathy
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批准号:6780912
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项目类别:
-
资助金额:$27.27万
-
财政年份:1997
-
负责人:Martin Hauer-Jensen
-
依托单位:
MOLECULAR PATHOGENESIS OF RADIATION ENTEROPATHY
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批准号:2010009
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项目类别:
-
资助金额:$19.11万
-
财政年份:1997
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负责人:Martin Hauer-Jensen
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依托单位:
Molecular Pathogenesis of Radiation Enteropathy
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批准号:8235062
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项目类别:
-
资助金额:$27.58万
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财政年份:1997
-
负责人:Martin Hauer-Jensen
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依托单位:
MOLECULAR PATHOGENESIS OF RADIATION ENTEROPATHY
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批准号:2668046
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项目类别:
-
资助金额:$19.69万
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财政年份:1997
-
负责人:Martin Hauer-Jensen
-
依托单位:
MOLECULAR PATHOGENESIS OF RADIATION ENTEROPATHY
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批准号:2882453
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项目类别:
-
资助金额:$20.28万
-
财政年份:1997
-
负责人:Martin Hauer-Jensen
-
依托单位: