Involvement of ALADIN in adrenal cell function and hormone and response

由AAAS基因编码的ALADIN是核孔复合物的组成部分。ALADIN在aaa综合征中功能失调，与严重的肾上腺功能不全有关。在患者中观察到的症状的多样性表明，不同的功能细胞途径参与了该疾病的发病机制。在第一个资助期，我们在三种不同的肾上腺模型中描述了肾上腺类固醇生成途径和肾上腺髓质功能的损害。我们的研究结果表明，肾上腺皮质细胞和髓质细胞之间存在一种依赖于ALADIN的串扰。我们现在计划确定潜在的信号分子，这是这种串扰所必需的。由于我们在人肾上腺细胞系NCI-H295R中观察到ALADIN下调和恢复后类固醇生成没有恢复，我们计划研究这些细胞的表观遗传变化，我们假设这是导致这种观察的原因。此外，我们将研究p38MAPK的改变作为应激诱导的早衰的一个方面。我们将研究ALADIN在Shh调控、增殖、细胞周期调控和凋亡中的作用。我们将研究ALADIN保护肾上腺细胞免受活性氧伤害的机制，并将测试抗氧化治疗的潜力。在细胞培养和我们的小鼠模型的原理证明之后，我们前瞻性地计划在我们世界上最大的aaa综合征患者队列中进行多中心临床试验。

ALADIN, encoded by the AAAS gene, is a component of the nuclear pore complex. ALADIN is dysfunctional in triple A syndrome, which is associated with severe adrenal insufficiency. The diversity of symptoms observed in patients suggests that different functional cellular pathways are involved in the pathogenesis of the disorder. In the first funding period we characterized the impairment of the adrenal steroidogenic pathway and adrenomedullary function in three different adrenal models. Our findings indicate that there is an ALADIN dependent crosstalk between adrenocortical and medulla cells. We now plan to identify potential signaling molecules, which are necessary for this crosstalk. Since we observed no rescue of steroidogenesis after downregulation and recovery of ALADIN in the human adrenal cell line NCI-H295R we plan to study epigenetic changes in these cells, which we hypothesize are the cause for this observation. Furthermore we will examine p38MAPK alterations as one aspect of stress-induced premature senescence. We will study the involvement of ALADIN in Shh regulation and in proliferation, cell cycle regulation and apoptosis. We will investigate mechanisms by which ALADIN protects the adrenal cells from reactive oxygen species and will test the potential of antioxidative treatment. After proof of principle in cell culture and our mouse models we prospectively plan a multicenter clinical trial in our world-largest cohort of triple A syndrome patients.