ADRENAL REGENERATION-- IMMUNO-ENDOCRINE INTERACTIONS

肾上腺再生——免疫内分泌相互作用

• 批准号: 6650317
• 负责人: WILLIAM C. ENGELAND
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650317
• 关键词: RNase protection assay; adrenal glands; adrenocorticotropic hormone; aldosterone; angiotensin II; angiotensin receptor; cell differentiation; cell growth regulation; cell proliferation; cytochrome P450; cytokine; gene expression; hormone regulation /control mechanism; immunocytochemistry; inflammation; laboratory rat; macrophage; messenger RNA; phenotype; protein protein interaction; receptor expression; regeneration; renin angiotensin system; tissue /cell culture; western blottings

The overall hypothesis is that adrenal regulation is dependent on a sequence of early cellular events that are characterized by phenotypic plasticity and mediated by interaction between local inflammatory and circulating endocrine factors. To test this hypothesis, three major questions will be addressed. First, what is the mechanism for ACTH-induced promotion of adrenal regeneration? Experiments will delineate the effect of ACTH suppression on phenotypic and proliferative changes in regenerating adrenals. Changes in expression of mRNA and protein for cytochrome P450 and aldosterone synthase, a P450 11beta-hydroxylase, will be used as phenotype markers of glomerulosa and fasiculata cells, respectively. Proliferation of specific cell phenotypes will be monitored using double-label immunohistochemistry that induces proliferation markers. Changes in adrenal melanocortin-2 receptor mRNA and protein will be examined using RNase protection and western analysis, respectively; immunohistochemistry will assess the cellular distribution of the receptor. Second, does the renin-angiotensin (AT) system act to suppress regeneration? Since AT upregulates adrenal P450 aldosterone synthase and promotes expansion of zona glomerulosa, studies will determine the role of specific AT receptor subtypes in regeneration using antagonists of the AT-1 and AT-2 receptors. Experiments will characterize the distribution and binding of AT-1 and AT-2 receptors in regenerating adrenals. Since AT has been implicated in models of fibrosis, studies will assess whether AT produces adrenal fibrosis. Third, what components of inflammatory responses affect adrenal regeneration? Since both adrenal and inflammatory cells can synthesize cytokines, the phenotype of cells expressing cytokine activity during regeneration will be delineated. Cytokines identified in regenerating adrenals including interleukin-1, interleukin-1 receptor antagonist, interleukin-18, macrophage migration inhibitory factory and transforming growth factor-beta will be examined in vitro. The effect of specific cytokines on adrenal cell differentiation and proliferation will be defined using short-term cultures of adrenal capsules with adherent cortical cells; potential cytokine modulation of ACTH and AT receptors will be evaluated. It is proposed that corticosteroids affect macrophage secretory activity at the site of adrenal inflammation. Studies using cultured regenerating adrenals or co-cultures of macrophages and adrenal capsules will assess macrophage-adrenal interactions. Since ACTH and AT may affect regeneration indirectly by altering the local inflammatory response, experiments will assess adrenal cytokine mRNA expression after in vivo blockade of ACTH or AT receptors. The proposed experiments should delineate the interaction between local inflammatory and endocrine factors responsible for adrenal regeneration and offer new perspective on injury-induced processes that result in tissue regeneration or fibrosis.

总体假设是肾上腺调节取决于 以表型为特征的早期细胞事件的序列 可塑性，并通过局部炎症和 循环内分泌因素。为了检验这一假设，三个主要问题 将被解决。首先，ACTH引起的促进的机制是什么 肾上腺再生？实验将描述ACTH抑制的效果 关于再生肾上腺的表型和增殖变化。变更 MRNA和蛋白质的细胞色素P450和醛固酮合酶的表达，A P450 11Beta-羟化酶将用作肾小球的表型标记和 Fasiculata细胞分别。特定细胞表型的增殖将 使用诱导增殖的双标签免疫组织化学来监测 标记。肾上腺黑色皮质素-2受体mRNA和蛋白质的变化将是 分别使用RNase保护和西方分析检查； 免疫组织化学将评估受体的细胞分布。 其次，肾素 - 血管紧张素（AT）系统是否可以抑制再生？ 因为在上调肾上腺P450醛固酮合酶并促进膨胀 Zona glomerulosa的研究将确定特异性在受体中的作用 使用AT-1和-2受体的拮抗剂再生的亚型。 实验将表征AT-1和AT-2的分布和结合 再生肾上腺中的受体。由于AT已与 纤维化，研究将评估是否产生肾上腺纤维化。第三，什么 炎症反应的成分会影响肾上腺再生？两者既是 肾上腺和炎性细胞可以合成细胞因子，这是细胞的表型 将描述在再生过程中表达细胞因子活性。细胞因子 在包括白介素-1，白介素-1的再生肾上腺中鉴定 受体拮抗剂，白介素-18，巨噬细胞迁移厂 并将在体外检查转化生长因子β。效果 关于肾上腺细胞分化和增殖的特定细胞因子将是 使用具有粘附皮质的肾上腺胶囊的短期培养 细胞； ACTH和AT受体的潜在细胞因子调节将是 评估。建议皮质类固醇会影响巨噬细胞分泌 肾上腺炎症部位的活性。使用培养的研究 巨噬细胞和肾上腺胶囊的再生肾上腺或共同培养 评估巨噬细胞 - 肾上腺相互作用。由于ACTH和可能会影响 通过改变局部炎症反应间接再生， 实验将评估体内阻滞后肾上腺细胞因子mRNA表达 ACTH或受体。提出的实验应描绘 局部炎症和内分泌因素之间的相互作用 肾上腺再生并就伤害引起的过程提供新的观点 导致组织再生或纤维化。

项目成果

Capsaicin-sensitive nerve fibers: a potential extra-ACTH mechanism participating in adrenal regeneration in rats.

辣椒素敏感神经纤维：参与大鼠肾上腺再生的潜在额外 ACTH 机制。

• DOI: 10.1002/jemt.10334
• 发表时间: 2003
• 期刊: Microscopy research and technique.
• 作者: Ulrich-Lai,YvonneM;Fraticelli,AdaI;Engeland,WilliamC
• 通讯作者: Engeland,WilliamC

Capsaicin-sensitive adrenal sensory fibers participate in compensatory adrenal growth in rats.

辣椒素敏感的肾上腺感觉纤维参与大鼠肾上腺的代偿性生长。

• DOI: 10.1152/ajpregu.00266.2002
• 发表时间: 2002
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Ulrich-Lai,YvonneM;Marek,DanielJ;Engeland,WilliamC
• 通讯作者: Engeland,WilliamC

Steroidogenic factor-1 is essential for compensatory adrenal growth following unilateral adrenalectomy.

• DOI: 10.1210/endo.143.8.8944
• 发表时间: 2002-08
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: F. Beuschlein;C. Mutch;David L. Bavers;Y. Ulrich‐Lai;W. Engeland;C. Keegan;G. Hammer