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

• 批准号: 9000699
• 负责人: BRUCE BLUMBERG
• 金额: $ 42.29万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/9000699
• 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; Health; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Hyperactive behavior; Immunity; In Vitro; Incidence; Individual; Inflammation; Knock-in; Knowledge; Lead; Life; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Modeling; Mus; NF-kappa B; Non-Hodgkin' 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; adaptive immunity; 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; receptor; receptor expression; receptor function; research study; sialic acid binding Ig-like lectin; therapeutic target

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-κB 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，旨在测试类固醇功能丧失和 异生素受体 SXR 将导致暴露个体患淋巴瘤和白血病。确定 SXR 在常见人类恶性肿瘤中的作用将直接将环境暴露与癌症联系起来，因为 SXR 会被多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 细胞增殖？（2）化学拮抗剂抑制 SXR 是否会导致 B-1 细胞和淋巴瘤增殖增加？（3）B-1 细胞增殖的发育调节何时需要 SXR 作用？我们的研究将在 SXR 功能丧失和淋巴癌之间建立联系，阐明我们对暴露于 PCB 等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，确定 SXR 在常见人类恶性肿瘤中的作用将环境暴露与癌症直接联系起来。接触内分泌干扰化学物质对人们来说是一个持续的风险；因此，这些实验将有助于阐明这些与环境相关的 SXR 调节剂导致淋巴瘤的机制。这些知识将有助于指导和集中未来的预防工作。 创新性这项研究的创新性在于，据我们所知，目前还没有人能够解释环境中暴露于 PCB 和 PBDE 等有机卤素化合物与非霍奇金淋巴瘤 (NHL) 等血癌之间的关系。我们发表的研究将 SXR 功能丧失与 NF-κB 过度活跃和慢性炎症联系起来，并且我们最近表明 SXR 功能丧失会导致小鼠 B-1a B 细胞淋巴瘤。我们采用创新的小鼠模型，即人源化 SXR 敲入 (hSXRki)，它在内源性小鼠启动子的控制下在全身表达人类 SXR。该模型使我们能够测试新的假设，即体内化学拮抗剂抑制 SXR 功能会导致淋巴增殖和淋巴瘤。