Molecular mechanisms of the developments of Graves' disease and diabetes mellitus ; O_2 production-DNA damage and their signal transductions

格雷夫斯病和糖尿病发生的分子机制；

• 批准号: 03807160
• 负责人: TAKASU Nobuyuki
• 金额: $ 1.22万
• 依托单位: University of the Ryukyus (1993)Shinshu University (1991-1992)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03807160/
• 关键词: Graves' disease; diabetes mellitus; thyroid; pancreatic B cells; O_2 production; DNA fragmentation; signal transduction; autoimmune endocrine diseases

There are many patients with Graves' disease and diabetes mellitus. Both Graves' disease and diabetes mellitus are autoimmune diseases. However, we do not know the molecular mechanisms of the developments of Graves' disease and diabetes mellitus. Thus we intended to reveal the molecular mechanisms of the developments of Graves' disease and diabetes mellitus, and found that O_2 production and consequent DNA fragmentation playd very important roles in the development of both diseases. We also studied the signal transduction systems of O_2 production and DNA fragmentation. We cultured thyroid cells and pancreatic islets and conducted many experiments.We obtained a clear evidence for the molecular mechanism of the development of diabetes mellitus. Streptozotocin and alloxan exhibit the most potent diabetogenecity, and have been used for induction of experimental diabetes mellitus. DNA fragmentation plays an important role for the development of diabetes. Our in vitro and vivo experiments demonstrated that streptozotocin and alloxan stimulated H_2O_2 generation, which induced DNA fragmentation. Streptozotocin and alloxan induce diabetes through the following biochemical events ; streptozotocin and alloxan->H_2O_2 generation->DNA fragmentation->diabetes. As a signal transduction system, Ca plays an important role in streptozotocin and alloxan->H_2O_2 generation->DNA fragmentation->diabetes.

Graves病合并糖尿病的患者很多。Graves病和糖尿病都是自身免疫性疾病。然而，我们对Graves病和糖尿病发生发展的分子机制还不清楚。因此，我们试图揭示Graves病和糖尿病发生发展的分子机制，发现O_2的产生及其引起的DNA断裂在两种疾病的发生发展中起着重要作用。我们还研究了O_2产生和DNA断裂的信号转导系统。本研究通过对甲状腺细胞和胰岛细胞的培养，进行了大量的实验研究，为糖尿病发生发展的分子机制提供了明确的证据。链脲佐菌素和四氧嘧啶具有最强的致糖尿病作用，已被用于诱导实验性糖尿病。DNA断裂在糖尿病的发生发展中起着重要作用。我们的体外和体内实验表明，链脲佐菌素和四氧嘧啶刺激H_2O_2产生，导致DNA断裂。链脲佐菌素和四氧嘧啶通过以下生化事件诱发糖尿病：链脲佐菌素和四氧嘧啶->H_2O_2生成->DNA断裂->糖尿病。Ca作为一种信号转导系统，在链脲佐菌素和四氧嘧啶->H_2O_2生成->DNA断裂->糖尿病中起重要作用。

项目成果

Takasu, N.et al.: "Development of autoimmune thyroid dysfunction after bilateral adrenalectomy in a patient with Carney's complex and after removal of ACTH-producing pituitary adenoma in a patient with Cushing's desease." Journal of Endocrinological Inves

Takasu, N.等人：“卡尼综合征患者双侧肾上腺切除术后以及库欣病患者切除产生 ACTH 的垂体腺瘤后出现自身免疫性甲状腺功能障碍。”

I.Komiya,N.Takasu,T.Yamada,et al.: "Studies on the association of NIDDM in Japanese patients with hyperthyroid Graves' disease" Hormone Research. 38. 264-268 (1993)

I.Komiya、N.Takasu、T.Yamada 等：“日本甲状腺功能亢进 Graves 病患者与 NIDDM 关联的研究”激素研究。

Takasu, N.et al.: "Disappearance of thyrotropin-blocking antibodies and spontaneous recovery from hypothyroidism in autoimmune thyroiditis." New England Journal of Medicine. 326. 513-518 (1992)

Takasu, N.等人：“自身免疫性甲状腺炎中促甲状腺素阻断抗体的消失和甲状腺功能减退症的自发恢复。”

Takasu, N.et al.: "Requirements of follicle structure for thyroid hormone synthesis ; cytoskeletons and iodine metabolism in polarized monolayr cells on collagen gel and in double layred, follicle-forming cells." Endocrinology. 131. 1143-1148 (1992)

Takasu, N.等人：“甲状腺激素合成对卵泡结构的要求；胶原凝胶上极化单层细胞和双层卵泡形成细胞的细胞骨架和碘代谢。”

Komiya, I., Takasu, N.et al.: "Studies on the association of NIDDM in Japanese patients with hyperthyroid Graves' disease." Hormone Research. 38. 264-268 (1993)

Komiya, I.、Takasu, N.等人：“日本甲状腺功能亢进格雷夫斯病患者与 NIDDM 相关性的研究。”