RXR-Heterodimeric Receptors in the GI Tract

描述（由申请人提供）：流行病学研究表明， 膳食脂肪营养素的量和含量影响 结肠癌过氧化物酶体增殖物激活受体（PPARs）是 类维生素A-X-受体（RXR）异二聚体家族的成员 转录调节因子，并激活基因转录，以响应 脂肪酸及其代谢物。PPAR-gamma和PPAR-delta（beta）在 结肠癌的发病机制中有牵连。PPAR必须 与RXR异源二聚化以结合DNA应答元件。RXR结合 9-顺式-视黄酸，其是维生素A代谢物，并且最近被 显示也结合二十二碳六烯酸。RXR也形成同二聚体， 为许多其他核受体提供义务伙伴， 肠上皮细胞因此，PPARs参与混合组装， 与RXR相互作用的受体。我们建议检验这个假设， RXR-PPAR异源二聚体在介导脂质营养中起重要作用 肠道细胞中的信号。我们建议直接测量RXR、PPAR和 在培养物中生长的肠细胞中的RXR-PPAR异二聚体水平，或 从小鼠结肠分离的上皮细胞。我们计划测量 通过使用在体外改变RXR-PPAR异二聚体形成的结果 Caco-2细胞，其来源于原发性人结肠癌， 通过使用基因工程小鼠模型体内。我们将搜索 RXR-α的突变和剪接变异体与人类 结肠癌了解RXR-PPAR的结构基础 我们将绘制PPAR-gamma中的最小肽结构域， 可以破坏RXR-PPAR相互作用。我们建议研究内异源二聚化 RXR与最小肽相互作用的核磁共振研究 技术.

DESCRIPTION (provided by applicant): Epidemiological studies indicate that the amount and content of dietary lipid nutrients influence the development of colon cancer. The peroxisomal proliferator activated receptors (PPARs) are members of the retinoid-x-receptor (RXR) heterodimeric family of transcriptional regulators, and activate gene transcription in response to fatty acids and their metabolites. PPAR-gamma and PPAR-delta (beta) are in the colon and have been implicated in the pathogenesis of colon cancer. PPARs must heterodimerize with RXRs in order to bind to DNA response elements. RXRs bind 9-cis-retinoic acids, which is a vitamin A metabolite, and has recently been shown to also bind docosahexaenoic acid. RXRs also form homodimers and are obligate partners for a number of other nuclear receptors that are in intestinal epithelial cells. Thus the PPARs participate in mixed assembly of receptors that interact with RXR. We propose to test the hypothesis that RXR-PPAR heterodimers play an important role in mediating lipid nutrient signals in intestinal cells. We propose to directly measure RXR, PPAR, and RXR-PPAR heterodimer levels in intestinal cells that are grown in culture, or epithelial cells isolated from mouse colons. We plan to measure the functional consequences of altering RXR-PPAR heterodimer formation in vitro by using Caco-2 cells, which are derived from a primary human colon carcinoma and in vivo by using genetically engineered mouse models. We will search for somatic mutations and splicing variants in RXR-alpha that are associated with human colon cancers. To understand the structural basis for RXR-PPAR heterodimerization we will map the minimal peptide domain in PPAR-gamma that can disrupt RXR-PPAR interactions. We propose to study intraheterodimerization interactions between RXR and the minimal peptide by nuclear magnetic resonance techniques.