Role Of Neuroendocrine Stress Response In Inflammatory A

SNIB研究下丘脑-垂体-肾上腺(HPA)轴在自身免疫性/炎症性疾病易感性和抵抗力中的各个方面的作用。主要的实验模型包括两个近交系大鼠(LOW/N和F344/N大鼠)，它们不同的HPA轴反应至少部分解释了它们不同的炎症易感性。最近的研究旨在确定决定这些菌株对自身免疫/炎症性疾病的不同易感性和抵抗力以及不同的促肾上腺皮质激素释放激素(CRH)反应的基因。之前的遗传连锁和分离研究现已终止，发现了两个连锁区域，一个位于10号染色体上的特定区域，另一个可能位于2号染色体上，与这些品系(LEW/N和F344/N大鼠)的炎症易感性或耐药性有关。位于10号染色体标记GH和R1710之间的与F344/N大鼠炎症抵抗相关的大区域(约16 cM)似乎与10号染色体上的Cia5和Oia3连锁区域相同，后者是15条染色体上约20个区域之一，与其他大鼠交叉杂交中的炎性关节炎有关。它还与老鼠11号染色体和人类17号染色体上的一个区域同步，该区域与啮齿动物和人类的其他自身免疫性疾病有关。与其他复杂的自身免疫性炎症性疾病的研究结果一致，这些遗传研究表明，基因对炎症性表型的贡献相对较低(约35%)，而环境变异相对较高(约65%)。该区域内的几个候选基因被测序，因为它们同时参与炎症和HPA轴调节(CRH-R1、ACE、STAT3、STAT5a和STAT5b)。这些基因显示出显着的编码区突变，单独似乎对表型没有影响。由于环境对该性状的贡献相对较高，我们研究了早期母婴相互作用作为可能的早期发育环境变量，该变量可能有助于这些菌株在成年期对炎症和HPA轴的不同反应。这些研究表明，压力、性别和早期母体环境相互作用并有助于成人HPA轴反应表型，而不是炎症性特征。用实时定量聚合酶链式反应、原位杂交和免疫组织化学对这些菌株中其他基因的调节进行评估，结果表明，下丘脑室旁核中的其他基因调控异常，这表明这些菌株对CRH的不同反应是由共同的细胞或信号因子而不是单一的神经激素基因造成的。

The SNIB studies various aspects of the role of the hypothalamic pituitary adrenal (HPA) axis in susceptibility and resistance to autoimmune/inflammatory disease. The main experimental model involves 2 inbred strains of rats (LEW/N and F344/N rats) whose differential HPA axis responsiveness accounts at least in part for their differential inflammatory susceptibilities. Recent studies are aimed at identifying genes involved in determining differential susceptibility and resistance to autoimmune/ inflammatory diseases and differential corticotropin releasing hormone (CRH) responsiveness in these strains. Prior genetic linkage and segregation studies, now terminated, identified two linkage regions, one definite region on chromosome 10 and one probable region on chromosome 2, that linked with inflammatory susceptibility or resistance in these rat strains (LEW/N and F344/N rats). The large (approximately 16 cM) region between markers GH and R1710 on chromosome 10 that linked to inflammatory resistance in F344/N rats appears to be identical to the Cia5 and Oia3 linkage regions on chromosome 10 that is one of approximately 20 regions on 15 chromosomes and links to inflammatory arthritis in other rat intercrosses. It is also syntenic with a region on mouse chromosome 11 and human chromosome 17 that link with other autoimmune diseases in rodents and humans. Consistent with findings in other complex autoimmune inflammatory diseases, these genetic studies indicated that the genotypic contribution to the inflammatory phenotype was relatively low (approximately 35%), and the environmental variation was relatively high (approximately 65%). Several candidate genes within this region were sequenced because they are involved in both inflammation and HPA axis regulation (CRH-R1, ACE, STAT3, STAT5a and STAT5b). These genes showed significant coding region mutations and alone did not appear to contribute to the phenotype. Because of the relatively high environmental contribution to the trait, we examined early maternal-pup interactions as a possible early developmental environmental variable that could contribute to the differential inflammatory and HPA axis responsiveness in these strains in adulthood. These studies indicated that strain, gender and early maternal environment interact and contribute to the adult HPA axis responsiveness phenotype but not to the inflammatory trait. Evaluation of regulation of other genes in these strains using real-time PCR, in situ hybridization and immunohistochemistry indicate that other genes are dysregulated in the paraventricular nucleus of the hypothalamus, suggesting that a common cellular or signaling factor and not a single neurohormone gene account for the differential CRH responsiveness in these strains.