Molecular Genetics Of Adrenocortical Tumors

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综合征和多发性内分泌缺陷引起的先天性肾上腺发育不良、家族性醛固酮增多症、肾上腺皮质癌和甲状腺癌、影响到垂体、甲状腺和肾上腺的垂体肿瘤和多发性内分泌肿瘤(MEN)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。这些项目是由Prkar1a特有的动物模型推动的。

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 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. These projects are facilitated by Prkar1a-specific animal models.