Molecular Genetics of Endocrine 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，遗传和与肾上腺发育不全或增生，多发性肿瘤和其他内分泌腺（特别是脑垂体和甲状腺）异常有关的疾病。我们研究了由三A综合征和其他缺陷引起的先天性肾上腺发育不全，其他多发性内分泌缺陷，家族性醛固酮增多症，肾上腺皮质癌和甲状腺癌，垂体瘤和多发性内分泌瘤（MEN）综合征影响垂体，甲状腺和肾上腺，以及Carney综合征（CNC），一种常染色体显性遗传病。CNC是一种影响垂体、肾上腺皮质、甲状腺和性腺的MEN综合征，并与多种其他肿瘤相关，包括粘液瘤和神经鞘瘤，以及皮肤色素沉着缺陷（雀斑、黑色素斑和痣）。我们已经确定了蛋白激酶A（PKA）的1-A型调节亚基，该亚基由PRKAR 1A基因编码，是大多数CNC患者的基因。因此，我们工作的一个重要部分现在集中在PKA刺激的信号通路，PKA对肿瘤抑制和/或发展的影响，细胞周期和染色体稳定性。还建立了Prkar 1a特异性动物模型，以解决该基因的肿瘤促进作用，并作为可能的治疗模型。此外，正在研究CNC-like和其他遗传性肾上腺肿瘤患者的基因突变。最近，在各种形式的双侧肾上腺皮质增生患者中发现了PRKACA、PRKACB和ARMC 5以及磷酸二酯酶基因-磷酸二酯酶11 A（PDE 11 A）和PDE 8B的突变。 PDE 11 A和PDE 8B缺陷的小鼠模型正在研究中，这些基因的突变正在其他内分泌肿瘤中寻找。我们还阐明了在神经-层他基斯综合征（CSS）的致病性遗传缺陷，我们继续寻找与CSS和类似疾病（Carney Triad）相关的肿瘤相关的基因。

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 PRKACA, PRKACB and ARMC5, as well as in phosphodiesterase genes - phosphodiesterase 11A (PDE11A) and PDE8B - were identified in patients with various forms of bilateral adrenocortical hyperplasias. Mouse models of PDE11A and PDE8B deficiency are being studied, and mutations of these genes are being sought in other endocrine tumors. We have also elucidated the causative genetic defects in Carney-Stratakis syndrome (CSS) and we continue our search for genes that are related to tumors that develop in association with CSS and a similar condition (Carney Triad).