Molecular Genetics Of Adrenocortical Tumors And Related Disorders

这项工作的目的是了解导致影响肾上腺皮质的疾病的遗传和分子机制，重点是那些发育性、遗传性和与肾上腺发育不全或增生、多发性肿瘤和其他内分泌腺（特别是垂体和甲状腺）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、垂体肿瘤和多发性内分泌瘤（MEN）综合征影响垂体、甲状腺和肾上腺，以及卡尼综合征（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、甲状腺和性腺的男性综合征，并与多种其他肿瘤相关，包括黏液瘤和神经鞘瘤，以及皮肤色素沉着缺陷（痣、咖啡色斑点和痣）。我们已经确定了蛋白激酶A （PKA）的调控亚基类型1-A，该基因由PRKAR1A基因编码，是大多数CNC患者的基因。因此，我们工作的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。prkar1特异性动物模型也已被创建，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，在患有cnc样和其他形式的遗传性肾上腺肿瘤的患者中发生突变的基因正在研究中。最近，在双侧肾上腺皮质增生患者中发现了磷酸二酯酶基因-磷酸二酯酶11A （PDE11A）和PDE8B的突变。目前正在研究PDE11A缺乏的小鼠模型，并在其他内分泌肿瘤中寻找该基因的突变。我们还开始了为PDE8B生成小鼠模型的工作。最近，我们已经阐明了卡尼- stratakis综合征（CSS）的致病遗传缺陷，并且我们已经开始了一项新的研究，寻找与CSS和类似疾病相关的肿瘤相关的基因（Carney Triad）。

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 genes - phosphodiesterase 11A (PDE11A) and PDE8B - 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. We also started the effort to generate a mouse model for PDE8B. Most recently, we have elucidated the causative genetic defects in Carney-Stratakis syndrome (CSS) and we have embarked on a new search for genes that are related to tumors that develop in association with CSS and a similar condition (Carney Triad).