TRH Production and Regulation by Human Melanoma

描述（由申请人提供）：候选人是一名获得博士学位的医学肿瘤学家。1998年在医学博士临床系获得学位。安德森癌症中心。1999年，她离开了她的临床教师职位，在生物免疫治疗系Elizabeth Grimm博士的实验室接受博士后研究员培训，获得了T32培训补助金（T32 CA 72371，Gabriel Lopez-Berestein博士）。候选人的长期职业目标是成为一名独立的研究人员和实验室负责人，该实验室专注于黑色素瘤生物和免疫治疗领域的转化研究。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具体目标;并通过R 01机制制定纵向研究计划。目的是在医学博士处开展拟议的研究。安德森癌症中心，组织资源可通过黑色素瘤肿瘤银行。这项研究计划是基于葡萄膜和皮肤黑色素瘤患者甲状腺功能减退症的高患病率的观察。据推测，黑色素瘤产生和分泌促甲状腺激素释放激素（TRH）作为一种自分泌生长因子，结合并激活黑皮质素-1受体（MC 1-R）;黑色素瘤的TRH产生受下丘脑中正常功能的TRH控制机制调节。这些机制包括通过低水平的循环甲状腺激素（甲状腺功能减退症）刺激TRH;通过瘦素受体的长同种型的瘦素水平升高的信号传导;以及通过黑皮质素-4受体（MC 4-R）的β-黑素细胞刺激激素信号传导。初步数据表明，TRH信息和蛋白质的存在下，原发性黑色素瘤和黑色素瘤细胞系。MC 1-R也已在这些品系中鉴定。第一个具体目标是验证TRH作为黑色素瘤自分泌生长因子的作用。在先前的实验中已经证明了黑色素瘤细胞表达TRH。将通过放射免疫测定法检测和定量分泌物。免疫共沉淀和cAMP的测量将建立TRH对MC 1-R的结合和激活。TRH对增殖和迁移的影响也将被检查。在具体目标#2中，细胞系将用于体外研究，以确定下丘脑TRH调节的一种或多种机制是否与黑色素瘤细胞的TRH产生控制相关。

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.