Cyclin D1 in oral carcinogenesis

描述(由申请人提供)： K22奖项的拟议计划是一年的学者阶段和四年的教师发展阶段。学者阶段将在康涅狄格大学健康中心安德鲁·阿诺德博士的实验室进行高级博士后培训。这一阶段的辅导式培训旨在让我将精力集中在研究和职业发展上。在此期间，我们将探讨甲状旁腺功能亢进症(HPT)的分子机制。甲状旁腺腺瘤的一个特点是对钙的敏感性丧失--这是对正常情况下甲状旁腺激素分泌与环境钙水平紧密结合的“设定点”机制的明显重置。在这些肿瘤中，荷尔蒙失调和增殖过程似乎有着不可阻挡的联系。然而，这些关键和一致的联系背后的机制尚不清楚。我们最近开发了一种初级HPT的小鼠模型。在这个模型中，我们已经证实，细胞周期蛋白D1的初级失控导致甲状旁腺的增殖和钙-甲状旁腺激素分泌关系的继发性紊乱。通过检测细胞周期蛋白D1对调节调节点的解除作用，将阐明甲状旁腺肿瘤中增殖和功能异常之间的关键联系。在我们的原发性HPT小鼠模型中，细胞周期蛋白D1的失控会导致甲状旁腺细胞增多和增大。然而，目前还不能确定这些腺体增大是多克隆增殖还是克隆性扩张。对这些病变的克隆性质的检测将有助于阐明细胞周期蛋白D1的致癌机制，并将为进一步研究甲状旁腺肿瘤发生的遗传调控奠定基础。为教师阶段提出的研究将研究口腔肿瘤进展的分子机制。这些研究将利用最近开发的上消化道癌症小鼠模型。在这个模型中，细胞周期蛋白D1的组织特异性失调导致舌头、食道和前胃的上皮不典型增生。该模型将用于研究口腔鳞状细胞癌发展过程中细胞周期蛋白D1的过度表达与化学致癌物的相互作用，以及细胞周期蛋白D1诱导的异型增生进展过程中发生的分子和遗传学事件。这些研究将有助于阐明细胞周期蛋白D1‘S在口腔癌前病变和恶变中的作用，以及口腔癌多步致癌过程中的分子事件。

DESCRIPTION (provided by applicant): The proposed plan for the K22 award is one year of the scholar phase and four years of the faculty development phase. The scholar phase will be spent pursuing advanced postdoctoral training in the laboratory of Dr. Andrew Arnold at the University of Connecticut Health Center. This phase of mentored training is designed to allow me to concentrate my efforts on research and career development. During this period, we will investigate the molecular mechanisms of hyperparathyroidism (HPT). A hallmark of parathyroid adenomas is their loss of calcium sensitivity--an apparent resetting of the 'setpoint' mechanism that normally tightly couples PTH secretion with ambient calcium levels. In these tumors, the processes of hormonal dysregulation and proliferation seem to be inexorably linked. However, the mechanisms that underlie these crucial and consistent links are not yet known. We have recently developed a mouse model of primary HPT. In this model, we have established that primary deregulation of cyclin D1 causes a secondary disturbance in parathyroid proliferation and in the calcium-PTH secretory relationship. Examination of the contribution of cyclin D1 to deregulation of setpoint control will elucidate the critical links between proliferation and functional abnormalities in parathyroid neoplasia. In our mouse model of primary HPT, cyclin D1 deregulation causes hypercellularity and enlargement of the parathyroid glands. However, it has not been established whether these glandular enlargements represent polyclonal proliferations or clonal expansions. Examination of the clonal nature of these lesions will shed light on the oncogenic mechanism of cyclin D1 and will form the basis for future studies on the genetic regulation of parathyroid tumorigenesis in this animal model of HPT. Research proposed for the faculty phase will study the molecular mechanisms of oral neoplastic progression. These studies will exploit a recently developed mouse model of upper aero-digestive cancer. In this model, tissue-specific dysregulation of cyclin D1 causes epithelial dysplasias in the tongue, esophagus and forestomach. This model will be used to study the interaction of cyclin D1 overexpression with chemical carcinogens in the development of oral squamous cell carcinoma, and the molecular and genetic events that occur during the progression of cyclin D1-induced dysplasias. These studies will elucidate our understanding of cyclin D1's role in oral premalignancy and malignancy and the molecular events in the multistep oral carcinogenic process.