Genetic analysis of the P13K/Akt pathway in thyroid benign and malignant disease

描述（由申请人提供）：甲状腺增生性疾病，从临床无症状的结节性增生到腺瘤性甲状腺肿，包括甲状腺癌，影响了美国大部分人口，女性的患病率高于男性。虽然大多数结节是良性的，但其中约5%会发展为恶性特征，仅凭形态学特征很难预测任何特定病变的命运。通过识别与结节生长增加或甲状腺去分化相关的途径，我们在高度流行的甲状腺结节疾病中预测或识别甲状腺癌的能力将大大提高。最近，大量临床数据表明PI3K/PTEN/AKT通路在甲状腺增生性疾病中起着至关重要的作用。该项目的长期目标是验证以下假设：PI3K/AKT通路的激活诱导良性甲状腺增生性疾病，它与雌激素信号串扰，决定女性较高的增殖指数和腺瘤发病率，并通过合作基因改变的发展促进恶性转化。我们建议在遗传定义的系统中通过直接的体内方法来验证这些假设，具体目的如下：目的1：表征PI3K/PTEN/AKT轴的激活在体内和体外诱导的小鼠甲状腺功能和分子改变。目的2：阐明循环雌激素增加雌性突变小鼠甲状腺细胞增殖和腺瘤易感性的机制。目的3：在体内和离体验证PI3K/AKT激活使甲状腺细胞克服Ras激活引发的抑制性反馈信号，从而诱导甲状腺细胞恶性转化的假设。公共卫生相关性：“甲状腺学”的终极挑战是在高度流行的甲状腺结节性疾病中预测甲状腺癌。因此，确定与结节生长增加或正在进行的甲状腺转化相关的途径将是理想的。我们的初步数据表明，体内慢性PI3K活性足以诱导甲状腺增生，并为肿瘤转化创造肥沃的土壤。因此，我们处于一个独特的位置，以实现在体内对甲状腺结节性疾病的发展及其进展为甲状腺滤泡性肿瘤的机制有更好的了解。

DESCRIPTION (provided by applicant): Thyroid proliferative disorders, ranging from clinically silent nodular hyperplasia to adenomatous goiter, and including thyroid cancer, affect a large part of the United States population, with a higher prevalence in women than in men. Although most nodules are benign, approximately 5% of them develop malignant features, and it is hard to predict the fate of any specific lesion, using only morphological features. Our ability to predict or identify thyroid cancer among the highly prevalent condition of nodular thyroid disease would be greatly improved by the identification of pathways that correlate with increased nodule growth or ongoing thyroid dedifferentiation. Numerous clinical data have recently pointed to the PI3K/PTEN/AKT pathway as a crucial player in thyroid proliferative disorders. The broad, long-term objective of this project is to test the hypotheses that activation of the PI3K/AKT pathway induces a benign thyroid hyperproliferative disorder, that it crosstalks with estrogen signaling to determine a higher proliferation index and increased adenoma incidence in females, and that it facilitates malignant transformation upon development of cooperating genetic alterations. We propose to test these hypotheses through a direct in vivo approach in a genetically defined system, with the following specific aims: Aim 1: To characterize in vivo and ex vivo the functional and molecular alterations induced in the mouse thyroid by the activation of the PI3K/PTEN/AKT axis. Aim 2: To elucidate the mechanisms through which circulating estrogens increase thyrocyte proliferation and adenoma susceptibility in female mutant mice. Aim 3: To test in vivo and ex vivo the hypothesis that PI3K/AKT activation allows thyroid cells to overcome inhibitory feedback signals initiated by Ras activation, thus inducing malignant thyrocyte transformation. PUBLIC HEALTH RELEVANCE: The ultimate challenge in "thyroidology" is the prediction of thyroid cancer among the highly prevalent condition of nodular thyroid disease. Thus it would be ideal to define pathways that correlate with increased nodule growth or ongoing thyroid transformation. Our preliminary data demonstrate that chronic PI3K activity is sufficient, in vivo, to induce thyroid hyperplasia and to create fertile ground for neoplastic transformation. Consequently we are in a unique position to achieve in vivo a better understanding of the mechanisms responsible for the development of nodular thyroid disease and its progression to thyroid follicular neoplasms.