Cyclin D1 in oral carcinogenesis

细胞周期蛋白 D1 在口腔癌发生中的作用

• 批准号: 6932347
• 负责人: SANJAY M MALLYA
• 金额: $ 13.48万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932347
• 关键词: calcium; cell proliferation; cyclins; disease /disorder model; histochemistry /cytochemistry; hyperparathyroidism; laboratory mouse; mouth neoplasms; neoplastic growth; parathyroid hormones; parathyroid neoplasms; polymerase chain reaction; postdoctoral investigator; receptor expression; southern blotting; squamous cell carcinoma

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.

描述（由申请人提供）： K22奖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的Andrew Arnold博士实验室进行高级博士后培训。这一阶段的指导培训旨在让我把精力集中在研究和职业发展上。在此期间，我们将研究甲状旁腺功能亢进（HPT）的分子机制。甲状旁腺腺瘤的一个标志是钙敏感性的丧失--一种明显的“设定点”机制的重置，该机制通常将PTH分泌与周围的钙水平紧密结合。在这些肿瘤中，激素失调和增殖的过程似乎是不可分割的联系。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原发性HPT的小鼠模型。在这个模型中，我们已经建立了原发性细胞周期蛋白D1失调引起甲状旁腺增生和钙-PTH分泌关系的继发性紊乱。检查细胞周期蛋白D1对设定点控制失调的贡献将阐明甲状旁腺肿瘤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失调导致甲状旁腺细胞过多和肿大。然而，还没有确定这些腺体扩大是否代表多克隆增殖或克隆扩张。这些病变的克隆性检查将揭示细胞周期蛋白D1的致癌机制，并将形成未来研究的基础上，在这种动物模型的HPT甲状旁腺肿瘤发生的遗传调控。教师阶段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呼吸消化道癌小鼠模型。在该模型中，细胞周期蛋白D1的组织特异性失调导致舌、食管和前胃的上皮发育不良。该模型将用于研究口腔鳞状细胞癌发展中细胞周期蛋白D1过表达与化学致癌物的相互作用，以及细胞周期蛋白D1诱导的发育不良进展过程中发生的分子和遗传事件。这些研究将阐明我们对细胞周期蛋白D1在口腔癌前病变和恶性肿瘤中的作用以及多步骤口腔致癌过程中的分子事件的理解。