Bladder transcriptome in experimental inflammation

实验性炎症中的膀胱转录组

基本信息

  • 批准号:
    6947847
  • 负责人:
  • 金额:
    $ 25.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-09-30 至 2008-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Interstitial Cystitis (IC) is a chronic bladder syndrome characterized by urinary urgency, frequency, nocturia pain and sterile urine. Although inflammation is not a universal characteristic of biopsies from IC patients, it seems that inflammation underline all major bladder pathologies including malignancy and represents a defense reaction to injury caused by physical damage, chemical substances, microorganisms or other gents. Indeed, areas of bladder inflammation are found in bladder disease including carcinoma, during chronic implantation of catheters, and an integrative part of bladder responses to intravesical Bacillus Calmette-Guerin (BCG). Although BCG has been proposed as a promising option for treatment of IC its mechanisms of action is not completely known. One of the theories is that intravesical BCG may be effective in treating by correcting an aberrant immune imbalance in the bladder, leading to long-term symptomatic improvement. It remains to be determined the nature of this immune imbalance. As nuclear factor kappaB (NFkappaB) has been described to modulate both bladder inflammation and the effects of BCG therapy, it is fair to propose, as a central hypothesis, that intravesical BCG leads to activation of NFkappaB and translation of pro- and anti-inflammatory genes that control both the immune and inflammatory system. The long-range goals of this application are to determine the gene networks involved in bladder responses to BCG therapy. To meet these goals, we will use the mouse as a vehicle for understanding basic biological questions regarding BCG and to permit rigorous control of experimental design. Transgenic mice with reporter genes expressed specifically on endothelial cells (Tie2-LacZ) and on promoter elements responsive to NFkappaB (p105-LacZ and p65-LacZ) will be used to address our hypothesis. In addition, the appropriate use of micro array technology combined with subtractive hybridization (SSH) will identify key molecules and mechanisms involved in the transition between acute and chronic inflammation in individual bladder layers. To address our central hypothesis, Aim 1 will quantify the time course alterations in bladder morphology as a consequence of acute and chronic intravesical BCG therapy. Aim 2 will test the hypothesis that NFkB plays a central role on BCG-induced bladder inflammation and Aim 3 will test the hypothesis that acute and chronic instillation of BCG induce a differential gene regulation in bladder mucosa and detrusor muscle. For this purpose, we will use micro array technology combined with suppression subtractive hybridization (SSH) to select bladder mucosa- and detrusor specific genes. Following target validation of SSH-selected genes, a custom array will be developed. This micro array will be used to determine how the bladder transcriptome is altered by BCG therapy.
描述(由申请人提供):间质性膀胱炎(IC)是一种慢性膀胱综合征,以尿急、尿频、夜尿痛和尿不育为特征。尽管炎症不是IC患者活检的普遍特征,但炎症似乎强调了包括恶性肿瘤在内的所有主要膀胱病理,并代表了对物理损伤、化学物质、微生物或其他物质引起的损伤的防御反应。事实上,膀胱炎症区域可在膀胱疾病(包括癌)、慢性置管期间以及膀胱对膀胱内卡介苗(BCG)反应的整体部分中发现。虽然卡介苗已被提出作为治疗IC的一个有希望的选择,但其作用机制尚不完全清楚。其中一种理论是膀胱内卡介苗可能通过纠正膀胱异常免疫失衡而有效治疗,从而导致长期症状改善。这种免疫失衡的性质还有待确定。由于核因子kappaB (NFkappaB)已被描述为调节膀胱炎症和卡介苗治疗的效果,因此可以公平地提出,作为一个中心假设,膀胱内卡介苗导致NFkappaB的激活以及控制免疫和炎症系统的促炎性和抗炎基因的翻译。这项应用的长期目标是确定参与膀胱对卡介苗治疗反应的基因网络。为了实现这些目标,我们将使用小鼠作为了解卡介苗基本生物学问题的载体,并允许严格控制实验设计。在内皮细胞(Tie2-LacZ)和NFkappaB启动子元件(p105-LacZ和p65-LacZ)上特异性表达报告基因的转基因小鼠将被用于验证我们的假设。此外,适当使用微阵列技术结合减法杂交(SSH)将确定个体膀胱层急性和慢性炎症过渡的关键分子和机制。为了解决我们的中心假设,Aim 1将量化急性和慢性膀胱内卡介苗治疗导致的膀胱形态学的时间变化。Aim 2将验证NFkB在BCG诱导的膀胱炎症中起核心作用的假设,Aim 3将验证急性和慢性灌注BCG诱导膀胱粘膜和逼尿肌差异基因调控的假设。为此,我们将使用微阵列技术结合抑制减法杂交(SSH)来选择膀胱粘膜和逼尿肌特异性基因。在ssh选择基因的目标验证之后,将开发定制阵列。这种微阵列将用于确定卡介苗治疗如何改变膀胱转录组。

项目成果

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RICARDO SABAN其他文献

RICARDO SABAN的其他文献

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{{ truncateString('RICARDO SABAN', 18)}}的其他基金

Urothelial Cell Physiology in Normal and Disease States
正常和疾病状态下的尿路上皮细胞生理学
  • 批准号:
    7001822
  • 财政年份:
    2005
  • 资助金额:
    $ 25.55万
  • 项目类别:
Bladder transcriptome in experimental inflammation
实验性炎症中的膀胱转录组
  • 批准号:
    6711583
  • 财政年份:
    2003
  • 资助金额:
    $ 25.55万
  • 项目类别:
Bladder transcriptome in experimental inflammation
实验性炎症中的膀胱转录组
  • 批准号:
    7277691
  • 财政年份:
    2003
  • 资助金额:
    $ 25.55万
  • 项目类别:
Bladder transcriptome in experimental inflammation
实验性炎症中的膀胱转录组
  • 批准号:
    7108526
  • 财政年份:
    2003
  • 资助金额:
    $ 25.55万
  • 项目类别:
Bladder transcriptome in experimental inflammation
实验性炎症中的膀胱转录组
  • 批准号:
    6803514
  • 财政年份:
    2003
  • 资助金额:
    $ 25.55万
  • 项目类别:
LPS-PEPTIDE INTERACTION IN BLADDER INFLAMMATION
LPS-肽在膀胱炎症中的相互作用
  • 批准号:
    2843580
  • 财政年份:
    1998
  • 资助金额:
    $ 25.55万
  • 项目类别:
LPS-Peptide Interaction in Bladder Inflammation
LPS-肽在膀胱炎症中的相互作用
  • 批准号:
    6802572
  • 财政年份:
    1998
  • 资助金额:
    $ 25.55万
  • 项目类别:
LPS-Peptide Interaction in Bladder Inflammation
LPS-肽在膀胱炎症中的相互作用
  • 批准号:
    6616412
  • 财政年份:
    1998
  • 资助金额:
    $ 25.55万
  • 项目类别:
LPS-Peptide Interaction in Bladder Inflammation
LPS-肽在膀胱炎症中的相互作用
  • 批准号:
    6709400
  • 财政年份:
    1998
  • 资助金额:
    $ 25.55万
  • 项目类别:
LPS-PEPTIDE INTERACTION IN BLADDER INFLAMMATION
LPS-肽在膀胱炎症中的相互作用
  • 批准号:
    6381546
  • 财政年份:
    1998
  • 资助金额:
    $ 25.55万
  • 项目类别:

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