SIGNALING CROSSTALK AND THYROID CELL SURVIVAL

信号串扰和甲状腺细胞存活

• 批准号: 6127551
• 负责人: JUDY L MEINKOTH
• 金额: $ 20.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6127551
• 关键词: CD95 molecule; apoptosis; cell line; cell transformation; cytokine; guanine nucleotide binding protein; hormone regulation /control mechanism; laboratory rat; oncogenes; thyroid gland; thyrotropin

Immune-mediated cell destruction is one of the central pathologic events in the development of autoimmune disease. In Hashimoto's thyroiditis (HT), a specific immune response to thyroid antigens leads to lymphocytic infiltration, follicular cell destruction and clinical hypothyroidism. It is now evident that apoptosis is one of the major pathologic mechanisms underlying HT and other forms of autoimmune disease. Proinflammatory cytokines are thought to play an initiating role in autoimmunity and apoptosis. Interferon-gamma (IFN-gamma) and interleukin 1-beta have been implicated in the pathogenesis of HT and other autoimmune disorders. Recently, these cytokines were shown to induce Fas receptor expression on normal human thyrocytes, cells that express FasL. Cross-linking of Fas resulted in massive apoptosis, leading to the speculation that following inflammation and cytokine release, thyroid cells are pruned to die by fratricidal mechanisms. Thyrotropin (TSH) regulates thyroid function, proliferation and possibly, survival. TSH stimulates the expression of thyroid-specific genes, effects that are opposed by (IFN-gamma). In turn, TSH has been reported to decrease IFN-gamma effects on Fas expression and apoptosis. Our aims are to elucidate the effects of proinflammatory cytokines in a continuous line of rat thyroid cells. We wish to explore the mechanisms of cytokine-induced cell death, and of survival promoted by TSH using a combination of biochemistry, cell biology and microinjection. Crosstalk between cytokines and hormones, given their opposing effects on Fas expression, may significantly alter the susceptibility of endocrine cells to apoptosis, a factor with profound implications for autoimmune diseases including thyroiditis, diabetes and rheumatoid arthritis. Ras activation, a frequent event in thyroid cancer, sensitizes many cells to cytokine-induced apoptosis, and numerous studies implicate a close linkage between signals activated by Ras and Fas. TSH appears to alter the balance in Ras-mediated signals from proliferation to apoptosis, a finding that may explain the infrequent occurrence of mutations in Ras and in Gs or the TSH receptor, mutations leading to the constitutive activity cAMP- mediated signaling pathways, in thyroid tumors. We will examine the acute effects of Ras on apoptosis, and the signaling pathways responsible for these effects. We will identify cellular factors that contribute to the ability of Ras-transformed cells to escape apoptosis. Taken together, these studies will provide new insight into the regulation of thyroid cell survival and transformation applicable to other endocrine cells.

免疫介导的细胞破坏是自身免疫性疾病发展的中心病理事件之一。 在桥本的甲状腺炎（HT）中，对甲状腺抗原的特定免疫反应会导致淋巴细胞浸润，卵泡细胞破坏和临床甲状腺功能减退症。 现在很明显，凋亡是HT和其他形式的自身免疫性疾病的主要病理机制之一。 促炎细胞因子被认为在自身免疫和凋亡中起发挥作用。干扰素 - 伽马（IFN-gamma）和白介素1-β已与HT和其他自身免疫性疾病的发病机理有关。 最近，这些细胞因子被证明可诱导正常人甲状腺细胞（表达FASL的细胞）上的Fas受体表达。 FA的交联导致大量细胞凋亡，导致猜测是在炎症和细胞因子释放后，甲状腺细胞被修剪为因术机制而死。 促甲状腺激素（TSH）调节甲状腺功能，增殖以及可能的生存。 TSH刺激甲状腺特异性基因的表达，其作用与（IFN-gamma）相反。 反过来，据报道，TSH降低了IFN-gamma对FAS表达和凋亡的影响。 我们的目的是阐明在大鼠甲状腺细胞连续系中促炎性细胞因子的作用。 我们希望探索细胞因子诱导的细胞死亡的机制，以及通过TSH使用生物化学，细胞生物学和显微注射的结合来促进的生存。 鉴于它们对FAS表达的影响，细胞因子和激素之间的串扰可能会显着改变内分泌细胞对凋亡的敏感性，这是对包括甲状腺炎，糖尿病和类风湿关节炎在内的自身免疫性疾病的深远影响。 RAS激活是甲状腺癌的常见事件，使许多细胞对细胞因子诱导的细胞凋亡敏感，许多研究暗示RAS和FAS激活的信号之间存在密切的联系。 TSH似乎会改变RAS介导的信号的平衡，从增殖到凋亡，这一发现可能解释了RAS和GS或GS或TSH受体中突变发生的很少发生的突变，突变导致甲状腺肿瘤中的本构成活性训练营介导的信号传导途径。 我们将检查RAS对凋亡的急性影响，以及负责这些影响的信号传导途径。 我们将确定有助于RAS转换细胞逃脱凋亡的能力的细胞因素。 综上所述，这些研究将为调节甲状腺细胞存活和适用于其他内分泌细胞的转化提供新的见解。