Intervention models for thyroid proliferative disease using a bioactive food comp

描述（由申请人提供）：全球有2亿人患有甲状腺增生性疾病（TPD），包括甲状腺肿、癌症和腺瘤。女性的易感程度是男性的三倍，总体而言，八分之一的女性患有甲状腺功能障碍，这是一个相当大的健康问题。甲状腺是一个血管化组织，新血管的细胞介质之一是骨髓来源的内皮祖细胞（CD31+, CD34+, VCAM+）。BM-EPCs通常存在于骨髓中，但在炎症、损伤或癌症反应时迁移到组织中，雌二醇（E2）增强了这种迁移。我们观察到雌二醇（E2）以E2依赖的方式增强外周循环和BM-EPCs向肿瘤组织的迁移，诱导新血管并上调细胞存活途径Akt和ERK。这些EPCs在E2的影响下迁移到组织中诱导血管生成，是抗雌激素治疗TPD的新靶点。我们建议在动物和细胞培养模型以及人类患者中测试抗雌激素DIM的活性，使用E2调节的血管发生和细胞存活途径Akt和ERK作为DIM作用的靶点。本研究的目的是：1 .在去卵巢（OVX） Balb/c/nu/nu小鼠中原位植入N-Thy-ori3-1（分化）、B-CPAP（未分化）、KAT50TS甲状腺肿大细胞系的异种移植动物模型中检测雌二醇诱导的新生血管。2。二、探讨E2-ER多蛋白复合物对BM-EPC和TPD细胞中Akt和ERK通路激活的调控及DIM可能的分子干预靶点。确定口服吸收增强制剂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.检测甲状腺组织中活化的Akt/ERK¿DIM的状态，通过基因阵列分析确定E2响应DIM介导的TPD分子变化，并在表达水平上进行验证。本基础转化研究旨在利用生物活性食品成分DIM减少TPD患者可能不必要的手术，并确定TPD性别偏见的细胞和分子基础。公共卫生相关性：这一具有新型基础成分的转化性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中可能不必要的手术。获得的手术组织将用于分析雌激素介导的功能，这可以阐明在女性中观察到的3:1的性别偏见。

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.