Involvement of ALADIN in adrenal cell function and hormone and response

ALADIN 参与肾上腺细胞功能和激素及反应

• 批准号: 202068324
• 负责人: Professorin Dr. Angela Hübner, Ph.D.
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/202068324?language=en
• 关键词: Involvement; ALADIN; adrenal; cell; function

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.

ALADIN 由 AAAS 基因编码，是核孔复合体的组成部分。 ALADIN 在与严重肾上腺功能不全有关的 3A 综合征中会出现功能障碍。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。在第一个资助期间，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伤。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阿拉丁依赖性串扰。我们现在计划识别这种串扰所必需的潜在信号分子。由于我们在人肾上腺细胞系 NCI-H295R 中 ALADIN 下调和恢复后没有观察到类固醇生成的挽救，因此我们计划研究这些细胞的表观遗传变化，我们假设这是这一观察结果的原因。此外，我们将检查 p38MAPK 的改变作为应激诱导的过早衰老的一个方面。我们将研究 ALADIN 在 Shh 调节以及增殖、细胞周期调节和细胞凋亡中的参与。我们将研究阿拉丁保护肾上腺细胞免受活性氧侵害的机制，并测试抗氧化治疗的潜力。在细胞培养和小鼠模型中进行原理验证后，我们前瞻性地计划在世界上最大的 3A 综合征患者群体中进行多中心临床试验。

项目成果

Organ-specific Neurodegeneration in Triple A syndrome-related Achalasia.

TripA综合征相关的贲门失弛缓症的器官特异性神经变性

• DOI: 10.1016/j.amjmed.2015.04.025
• 发表时间: 2015
• 期刊: The American journal of medicine
• 作者: Zimmer V;Vanderwinden JM;Zimmer A;Ostertag D;Strittmatter M;Koehler K;Huebner A;Lammert F
• 通讯作者: Lammert F

Computational analysis of liquid chromatography-tandem mass spectrometric steroid profiling in NCI H295R cells following angiotensin II, forskolin and abiraterone treatment

• DOI: 10.1016/j.jsbmb.2015.09.038
• 发表时间: 2016-01-01
• 期刊: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
• 影响因子: 4.1
• 作者: Mangelis, Anastasios;Dieterich, Peter;Eisenhofer, Graeme
• 通讯作者: Eisenhofer, Graeme

A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima

• DOI: 10.1136/jmedgenet-2016-104108
• 发表时间: 2017-03-01
• 期刊: JOURNAL OF MEDICAL GENETICS
• 影响因子: 4
• 作者: Koehler, Katrin;Milev, Miroslav P.;Sacher, Michael
• 通讯作者: Sacher, Michael

Triple A Syndrome: Preliminary Response to the Antioxidant N-Acetylcysteine Treatment in a Child

• DOI: 10.1159/000465520
• 发表时间: 2017-01-01
• 期刊: HORMONE RESEARCH IN PAEDIATRICS
• 影响因子: 3.2
• 作者: Barisson Villares Fragoso, Maria Candida;de Albuquerque Albuquerque, Edoarda Vasco;Mendonca, Berenice Bilharinho
• 通讯作者: Mendonca, Berenice Bilharinho