Endocrine disrupter modulation of SXR in development and lymphomagenesis

SXR 在发育和淋巴瘤发生中的内分泌干扰物调节

基本信息

批准号：
8506925
负责人：
BRUCE BLUMBERG
金额：
$ 34.63万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506925
关键词：
Adult Affinity Age-Months B lymphoid malignancy B-Cell Lymphomas B-Lymphocytes Cell Proliferation Cells Chemicals Chronic Cues Data Development Diet Disease Down-Regulation Drug usage Endocrine Disruptors Environment Environmental Exposure Exhibits Exposure to Fetal Liver Future Gene Expression Gene Targeting Genes Growth Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Human Hyperactive behavior Immune response Immunity In Vitro Incidence Individual Inflammation Knock-in Mouse Knowledge Lead Life Link Lymphocyte Lymphoma Lymphomagenesis Malignant Neoplasms Modeling Mus NF-kappa B Non-Hodgkin&apos s Lymphoma Nuclear Hormone Receptors PTPN6 gene Pathway interactions Pharmaceutical Preparations Play Polybrominated Biphenyls Polychlorinated Biphenyls Population Pregnancy Prevalence Prevention Publishing Regulation Research Risk Role SXR receptor Secure Signal Pathway Specificity Testing Tumor Suppressor Genes Tumor Suppressor Proteins Work Xenobiotics base cancer chemoprevention chemical group environment related cancer environmental chemical exposed human population forging immune function in vivo innovation leukemia/lymphoma loss of function lymphatic cancer mouse model novel phenyl ether progenitor promoter public health relevance receptor receptor expression receptor function research study sialic acid binding Ig-like lectin therapeutic target

项目摘要

DESCRIPTION (provided by applicant): This is an R01 application intended to test the hypothesis that loss-of-function in the steroid and xenobiotic receptor, SXR, will lead to lymphoma and leukemia in exposed individuals. Establishing a role for SXR in common human malignancies will directly link environmental exposures and cancer because SXR is activated or antagonized by a variety of drugs and environmental chemicals. Three specific aims are proposed: (1) How does SXR loss-of-function lead to proliferation of B-1cells?, (2) Does inhibition of SXR by chemical antagonists lead to increased proliferation of B-1 cells and lymphoma?, (3) When is SXR action required in the developmental regulation of B-1 cell proliferation? Our studies will forge a link between SXR loss-of-function and lymphatic cancers, illuminating our understanding of how exposure to environmental chemicals such as PCBs alters gene expression to increase the risk of lymphoma and leukemia. Therefore, establishing a role for SXR in common human malignancies directly links environmental exposures and cancer. Exposure to endocrine disrupting chemicals is a continuing risk to the population; hence, these experiments will aid in elucidating a mechanism through which these environmentally relevant SXR modulators contribute to lymphomas. This knowledge will help to guide and focus future prevention efforts. Innovation The proposed research is innovative in that, to our knowledge, no one has yet provided a mechanistic link for how environmental exposures to organohalogen compounds such as PCBs and PBDEs are linked to blood cancers such as non-Hodgkin's lymphoma (NHL). Our published studies link SXR loss-of-function with NF-?B hyperactivity and chronic inflammation and we recently showed that SXR loss-of-function leads to a B-1a B cell lymphoma in mice. We employ an innovative mouse model, the humanized SXR knock-in (hSXRki) that expresses human SXR throughout the body under the control of the endogenous mouse promoter. This model allows us to test the novel hypothesis that inhibition of SXR function by chemical antagonists, in vivo, leads to lymphoproliferation and lymphoma.

描述（由申请人提供）：这是一个R01应用程序，旨在检验类固醇中功能丧失和 SXR异生物受体将导致暴露的个体中淋巴瘤和白血病。建立SXR在普通人类恶性肿瘤中的作用将直接连接环境暴露和癌症，因为SXR被各种药物和环境化学物质激活或拮抗。提出了三个具体目标：（1）SXR功能丧失如何导致B-1细胞的增殖？（2）化学拮抗剂对SXR的抑制是否导致B-1细胞和淋巴瘤的增殖增加？我们的研究将建立SXR功能丧失与淋巴结癌之间的联系，从而阐明我们对PCBSCBS（PCB）暴露于环境化学物质如何改变基因表达以增加淋巴瘤和白血病风险的理解。因此，确立SXR在共同人类恶性肿瘤中的作用直接将环境暴露和癌症联系起来。暴露于内分泌破坏化学物质是人群的持续风险。因此，这些实验将有助于阐明这些与环境相关的SXR调节剂有助于淋巴瘤的机制。这些知识将有助于指导和集中未来的预防工作。创新拟议的研究具有创新性，据我们所知，还没有人提供机械链接，以了解环境对PCB和PBDES（例如PCB和PBDES）如何与非霍奇金淋巴瘤（NHL）等血液癌相关。我们发表的研究将SXR功能丧失与NF-？B多动和慢性炎症联系起来，我们最近表明SXR功能丧失导致小鼠的B-1A B细胞淋巴瘤。我们采用创新的小鼠模型，即人源化的SXR敲入（HSXRKI），该模型在内源性小鼠启动子的控制下表达人类SXR。该模型使我们能够检验一个新的假设，即化学拮抗剂在体内抑制SXR功能会导致淋巴增生和淋巴瘤。