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：
9212140
负责人：
BRUCE BLUMBERG
金额：
$ 36.49万
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 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212140
关键词：
Adult Affinity Age-Months B lymphoid malignancy B-Cell Lymphomas B-Lymphocytes Cell Compartmentation Cell Proliferation Cells Chemicals Chronic Clinical 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 Immunity In Vitro Incidence Individual Inflammation Knock-in 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 Teratogens Testing Tumor Suppressor Genes Tumor Suppressor Proteins Work Xenobiotics adaptive immune response base cancer chemoprevention chemical group environment related cancer environmental chemical experimental study exposed human population 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 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-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 R01 的预期应用，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。建立 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：（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 细胞增殖增加和淋巴瘤？, (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，阐明我们对暴露于环境化学物质（如由于 PCB 会改变基因表达，增加患淋巴瘤和白血病的风险，因此，确定 SXR 在常见人类恶性肿瘤中的作用与环境暴露和癌症直接相关。因此，这些实验将有助于阐明这些与环境相关的 SXR 调节剂促进淋巴瘤的机制，这些知识将有助于指导和集中未来的预防工作。我们已发表的研究链接还提供了一种机制，说明 PCB 和 PBDE 等有机卤素化合物的环境暴露与非霍奇金淋巴瘤 (NHL) 等血癌之间的关系。 SXR 功能丧失会导致 NF-κB 过度活跃和慢性炎症，我们最近发现 SXR 功能丧失会导致小鼠出现 B-1a B 细胞淋巴瘤。我们采用了一种创新的小鼠模型，即人源化 SXR 敲入模型。（hSXRki）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化学拮抗剂在体内抑制 SXR 功能的新假设。淋巴组织增生和淋巴瘤。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

妊娠 X 受体敲除小鼠表现出与年龄相关的关节软骨磨损。

DOI：
发表时间：
2015
期刊：
影响因子：
3.7
作者：
Azuma, Kotaro;Casey, Stephanie C;Urano, Tomohiko;Horie;Ouchi, Yasuyoshi;Blumberg, Bruce;Inoue, Satoshi
通讯作者：
Inoue, Satoshi

Obesity and endocrine-disrupting chemicals.

肥胖和内分泌干扰化学物质。

DOI：
发表时间：
2021-02
期刊：
影响因子：
2.9
作者：
Amato, Angelica Amorim;Wheeler, Hailey Brit;Blumberg, Bruce
通讯作者：
Blumberg, Bruce

Correction to: Parma consensus statement on metabolic disruptors.

更正：关于代谢干扰物的帕尔马共识声明。

DOI：
发表时间：
2017-12-06
期刊：
影响因子：
0
作者：
Heindel, Jerrold J;Vom Saal, Frederick S;Blumberg, Bruce;Bovolin, Patrizia;Calamandrei, Gemma;Ceresini, Graziano;Cohn, Barbara A;Fabbri, Elena;Gioiosa, Laura;Kassotis, Christopher;Legler, Juliette;La Merrill, Michele;Rizzi, Laura;Machtinger
通讯作者：
Machtinger

Environmental Obesogens: Mechanisms and Controversies.

环境致肥胖因素：机制和争议。