TRH Production and Regulation by Human Melanoma

人类黑色素瘤的 TRH 产生和调节

• 批准号: 6772894
• 负责人: JULIE A ELLERHORST
• 金额: $ 15.77万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772894
• 关键词: SDS polyacrylamide gel electrophoresis; autocrine; cell line; cell migration; cell proliferation; clinical research; growth factor; hormone biosynthesis; hormone metabolism; hormone receptor; hormone regulation /control mechanism; hormone related neoplasm /cancer; human tissue; hypothalamus; immunoprecipitation; leptin; melanocyte stimulating hormone; melanoma; neoplastic cell; neoplastic growth; radioimmunoassay; receptor binding; secretion; thyroid hormones; thyrotropin releasing hormone

DESCRIPTION (provided by applicant): The candidate is a medical oncologist who obtained a Ph.D. degree in 1998 while on clinical faculty at the M.D. Anderson Cancer Center. In 1999, she left her clinical faculty position to train as a postdoctoral fellow in the laboratory of Dr. Elizabeth Grimm, Department of Bioimmunotherapy, under a T32 training grant (T32 CA72371, Dr. Gabriel Lopez-Berestein). The long-term career goal of the candidate is to become an independent researcher and head of a laboratory that is focused on translational research in the area of biologic and immunologic therapy for melanoma. The immediate goals of the applicant are to develop a research plan, obtain funding, and carry out that plan to achieve the proposed specific aims; and to develop a longitudinal research plan with funding through the R01 mechanism. The intent is to carry out the proposed research at the M.D. Anderson Cancer Center, with tissue resources available through the Melanoma Tumor Bank. The research proposal is based on the observation of a high prevalence of hypothyroidism among patients with uveal and cutaneous melanoma. It is hypothesized that melanomas produce and secrete thyrotropin-releasing hormone (TRH) as an autocrine growth factor that binds and activates the melanocortin-1 receptor (MC1-R); and that TRH production by melanomas is regulated by TRH control mechanisms functioning normally in the hypothalamus. These mechanisms include stimulation of TRH by low levels of circulating thyroid hormone (hypothyroidism); elevated levels of leptin, signaling through the long isoform of the leptin receptor; and (-melanocyte stimulating hormone signaling through the melanocortin-4 receptor (MC4-R). Preliminary data demonstrate the presence of TRH message and protein in primary melanomas and melanoma cell lines. MC1-R has also been identified in these lines. The first specific aim proposes to verify the role of TRH as an autocrine growth factor for melanoma. Expression of TRH by melanoma cells has been demonstrated in previous experiments. Secretion will be detected and quantified by radioimmunoassay. Co-immunoprecipitation and measurement of cAMP will establish binding and activation of MC1-R by TRH. Effects of TRH on proliferation and migration will also be examined. In Specific Aim #2, cell lines will be used for in vitro studies to determine if one or more of the mechanisms of hypothalamic TRH regulation are relevant to the control of TRH production by melanoma cells.

描述（由申请人提供）：候选人是获得博士学位的医学肿瘤科医生。 1998年的学位，在医学博士安德森癌症中心的临床教职员工任职期间。 1999年，她离开了临床教师职位，在T32培训补助金（T32 CA72371，Gabriel Lopez-Berestein博士）下，在生物免疫疗法系伊丽莎白·格里姆（Elizabeth Grimm）博士的实验室研究员培训。候选人的长期职业目标是成为一名独立研究人员和实验室负责人，该研究人员专注于黑色素瘤生物和免疫学疗法领域的转化研究。申请人的直接目标是制定研究计划，获得资金并执行该计划，以实现拟议的特定目标；并通过R01机制通过资金制定纵向研究计划。目的是在M.D. Anderson癌症中心进行拟议的研究，并通过黑色素瘤肿瘤库提供组织资源。该研究建议是基于观察到紫veal和皮肤黑色素瘤患者中甲状腺功能减退症的高患病率。假设黑色素瘤会产生并分泌促甲状腺蛋白释放激素（TRH）作为结合和激活黑色素皮质素-1受体（MC1-R）的自分泌生长因子；黑色素瘤的TRH产生受下丘脑中正常起作用的TRH控制机制的调节。这些机制包括通过低循环甲状腺激素刺激TRH（甲状腺功能减退症）；瘦素水平升高，通过瘦素受体的长同工型信号传导； （ - 甲状腺细胞通过黑素皮质素-4受体刺激激素信号传导（MC4-R）。初步数据证明了原代黑色素瘤和黑色素瘤细胞系中的TRH消息和蛋白质的存在。在这些系中也已经鉴定出MC1-R。特定的目的是在以前的实验中证明了TRH作为黑色素瘤表达的作用。 TRH对MC1-R的激活也将在特定的AIM＃2中检查。控制黑色素瘤细胞对TRH产生的控制。