Intervention models for thyroid proliferative disease using a bioactive food comp

描述(申请人提供)：全球有2亿人受到甲状腺增生性疾病(TPD)的影响，包括甲状腺肿大、癌症和腺瘤。女性对甲状腺功能障碍的易感性是男性的三倍，总体而言，每八名女性中就有一人发生甲状腺功能障碍，这是一个相当大的健康问题。甲状腺是一种血管化组织，骨髓来源的内皮祖细胞(CD31+、CD34+、VCAM+)是新血管形成的细胞介质之一。BM-EPC通常驻留在骨髓中，但在炎症、损伤或癌症发生时会迁移到组织中，而雌二醇(E2)会加强这种迁移。我们观察到雌二醇(E_2)以一种依赖于E_2的方式增强外周循环和BM-EPC向肿瘤组织的迁移，诱导新生血管形成，并上调细胞存活途径Akt和ERK。这些内皮祖细胞在雌激素的影响下迁移到组织中诱导血管生成，是TPD抗雌激素治疗的新靶点。我们建议在动物和细胞培养模型中以及在人类患者中测试抗雌激素DIM的活性，使用E2调节的血管生成和细胞生存途径Akt和ERK作为DIM作用的靶点。本研究的目的是：1.采用异种移植动物模型，将N-Thy-ori3-1(已分化)、B-CPAP(未分化)、KAT50TS甲状腺肿细胞系移植到去卵巢(OVX)Balb/c/nu/nu小鼠体内，观察雌二醇诱导的新生血管形成。II.检测E2-ER多蛋白复合体对BM-EPC和TPD细胞Akt和ERK通路激活的调节以及DIM可能的分子干预靶点。确定口服吸收增强型DIM(生物反应DIM)是否达到足够的甲状腺组织生物利用度，并检查患者血液和尿液中的DIM水平。IV.检测甲状腺组织中激活的Akt/ERK？dim的状态，并通过基因芯片分析确定E2响应的dim介导的TPD分子变化的图谱，然后在表达水平上进行验证。这项基础的转化研究旨在使用生物活性食品成分DIM减少TPD可能进行的不必要手术，并确定TPD性别偏见的细胞和分子基础。公共卫生相关性：这项具有新的基本成分的转化研究旨在使用生物活性食品成分二吲哚甲烷DIM减少甲状腺增生性疾病可能进行的不必要手术。获得的手术组织将被用来分析雌激素介导的功能，这些功能可以阐明观察到的女性这种疾病发病率的3：1性别偏见。

DESCRIPTION (provided by applicant): Two hundred million people worldwide are affected by thyroid proliferative diseases (TPD), which include goiter, cancer and adenoma. Women are three times more susceptible than men and overall the incidence of thyroid dysfunction occurring in one in eight women is a sizable health issue. The thyroid is a vascularized tissue and one of the cellular mediators of neo-vasculature are bone marrow derived endothelial progenitor cells (CD31+, CD34+, VCAM+). BM-EPCs normally reside in the marrow but migrate to tissues in response to inflammation, injury or cancer and estradiol (E2) enhances this migration. We observed that estradiol (E2) enhances peripheral circulation and migration of BM-EPCs to tumor tissues, induces neo-vasculature and up regulates cell survival pathways, Akt and ERK, in an E2 dependent manner. These EPCs that migrate to tissues under the influence of E2 to induce vasculogenesis are novel targets of anti-estrogen therapy in TPD. We propose to test the activity of the anti-estrogen DIM in animal and cell culture models and in human patients using E2 regulated vasculogenesis and cell survival pathways, Akt and ERK, as targets of DIM action. The aims are to: I. Examine estradiol induced neovasculature using a xenograft animal model with orthotopic implantation of N-Thy-ori3-1(differentiated), B-CPAP (undifferentiated), KAT50TS goiter cell lines in ovariectomized (OVX) Balb/c/nu/nu mice ¿ E2 supplementation ¿ DIM incorporated in the diet. II. Examine the regulation of the activation of Akt and ERK pathway in BM-EPC and TPD cells by E2-ER multiprotein complexes and the possible molecular intervention targets of DIM. III. Determine if oral administration of an absorption-enhanced formulation of DIM (Bioresponse DIM) achieves adequate thyroid tissue bioavailability and examine DIM levels in blood and urine of patients. IV. Examine the status of activated Akt/ERK ¿ DIM in thyroid tissue and define the profile of E2 responsive DIM mediated molecular changes in TPD by gene array analysis followed by validation at the expression level. This basic translational research is directed to reduce possible unnecessary surgery in TPD using bioactive food component, DIM, and determining the cellular and molecular basis of the gender bias of TPD. PUBLIC HEALTH RELEVANCE: This translational research with a novel basic component is directed to reduce possible unnecessary surgery in thyroid proliferative diseases using bioactive food component, Diindolylmethane, DIM. Surgical tissues obtained will be used to analyze estrogen mediated functions that can shed light on the observed 3:1 gender bias in the incidence of this disease in women.