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，从临床上无症状的结节性增生到腺瘤性甲状腺肿，包括甲状腺癌，影响大部分美国人口，女性患病率高于男性。虽然大多数结节是良性的，但其中约5%发展为恶性特征，仅使用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持续的甲状腺去分化相关的通路，我们在结节性甲状腺疾病的高度流行状况中预测或识别甲状腺癌的能力将大大提高。许多临床数据最近指出PI 3 K/PTEN/AKT通路是甲状腺增殖性疾病的关键参与者。该项目的广泛的长期目标是测试PI 3 K/AKT通路的激活诱导良性甲状腺过度增殖性疾病的假设，其与雌激素信号传导交叉以确定女性中更高的增殖指数和增加的腺瘤发病率，并且其在协同遗传改变的发展后促进恶性转化。我们建议测试这些假设，通过直接在体内的方法在遗传定义的系统，具有以下具体目标：目的1：为了表征在体内和体外的功能和分子的变化诱导小鼠甲状腺的PI 3 K/PTEN/AKT轴的激活。目标二：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。目标3：为了在体内和离体测试PI 3 K/AKT激活允许甲状腺细胞克服由Ras激活引发的抑制性反馈信号，从而诱导恶性甲状腺细胞转化的假设。公共卫生相关性：甲状腺学的最终挑战是在结节性甲状腺疾病的高度流行状况中预测甲状腺癌。因此，它将是理想的，以确定相关的途径，增加结节生长或正在进行的甲状腺转化。我们的初步数据表明，慢性PI 3 K活性是足够的，在体内，诱导甲状腺增生，并创造肥沃的土壤肿瘤转化。因此，我们处于独特的地位，以实现在体内更好地了解负责结节性甲状腺疾病的发展及其进展为甲状腺滤泡性肿瘤的机制。

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.