Molecular Genetics Of Adrenocortical Tumors And Related Disorders

这项工作的目标是了解导致影响肾上腺皮质的疾病的遗传和分子机制，重点是那些发育、遗传性和与肾上腺发育不良或增生、多发性肿瘤和其他内分泌腺(特别是脑下垂体，程度较轻的甲状腺)的异常有关的疾病。我们研究了由AAA综合征和其他缺陷引起的先天性肾上腺发育不良、其他多重内分泌缺陷、家族性醛固酮增多症、肾上腺皮质癌和甲状腺癌、影响垂体、甲状腺和肾上腺的垂体肿瘤和多发性内分泌肿瘤(MENS)综合征，以及常染色体显性遗传病Carney综合征(CnC)。CnC是一种男性综合征，影响到垂体、肾上腺皮质、甲状腺和性腺，并与各种其他肿瘤有关，包括粘液瘤和神经鞘瘤，以及皮肤色素沉着缺陷(雀斑、咖啡斑和痣)。我们已经确定由PRKAR1A基因编码的蛋白激酶A(PKA)的调节亚单位1-A是大多数CNC患者的致病基因。因此，我们现在的工作主要集中在PKA刺激的信号通路，PKA在肿瘤抑制和/或发展中的作用，细胞周期和染色体稳定性。Prkar1a特异的动物模型也已经被创建，以解决该基因的肿瘤促进作用，并作为可能的治疗方法的模型。此外，遗传性肾上腺肿瘤患者和其他遗传性肾上腺肿瘤患者中突变的基因正在进行研究。最近，在双侧肾上腺皮质增生症患者中发现了磷酸二酯酶基因-磷酸二酯酶11A(PDE11A)的突变。PDE11A缺乏症的小鼠模型正在研究中，该基因的突变正在其他内分泌肿瘤中寻找。

The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands (especially the pituitary gland and to a lesser extent the thyroid gland). We have studied congenital adrenal hypoplasia caused by triple A syndrome and other defects, other multiple endocrine deficiencies, familial hyperaldosteronism, adrenocortical and thyroid cancer, pituitary tumors and multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid and adrenal glands, and Carney complex (CNC), an autosomal dominant disease. CNC is a MEN syndrome affecting the pituitary, adrenal cortex, thyroid, and the gonads, and is associated with a variety of other tumors, including myxomas and schwannomas, and skin pigmentation defects (lentigines, cafe-au-lait spots, and nevi). We have identified the regulatory subunit type 1-A of protein kinase A (PKA), which is coded by the PRKAR1A gene as the gene responsible for most CNC patients. Thus, a significant part of our work is now focused on PKA-stimulated signaling pathways, PKA effects on tumor suppression and/or development, the cell cycle and chromosomal stability. Prkar1a-specific animal models have also been created to address the tumor-promoting effects of this gene and serve as models for possible therapies. In addition, genes that are mutated in patients with CNC-like and other froms of inherited adrenal tumors are being investigated. Most recently, mutations in a phosphodiesterase gene - phosphodiesterase 11A (PDE11A), were identified in patients with bilateral adrenocortical hyperplasia. A mouse model of PDE11A deficiency is being studied, and mutations of this gene are being sought in other endocrine tumors.