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SLC5A8 is a conditional tumor suppressor in colon linked to dietary fiber content

SLC5A8 是结肠中的一种条件性肿瘤抑制因子，与膳食纤维含量有关

基本信息

批准号：
9751215
负责人：
VADIVEL GANAPATHY
金额：
$ 33.93万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751215
关键词：
Adrenergic alpha-Antagonists Affinity Anti-inflammatory Automobile Driving Azoxymethane Biological Biological Models Blood Butyrates CD4 Positive T Lymphocytes Cells Colitis Colon Colon Carcinoma Coupled Data Dendritic Cells Diet Dietary Fiber Diffuse Ecology Epigenetic Process Epithelial Cells Exposure to Face Fermentation Fiber Generations Genes Genotype Goals Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Immune Immunosuppressive Agents In Vitro Inflammation Inflammatory Intake Interferon Type II Knockout Mice Lamina Propria Link Logic Maintenance Mammary gland Mediating Modeling Molecular Mucosal Immune System Mucous Membrane Mus Myeloid Cells Pathway interactions Phenotype Phylogenetic Analysis Process Regulatory T-Lymphocyte Role Severities Signal Transduction Sodium Dextran Sulfate T-Lymphocyte Testing Tretinoin Tumor Suppressor Proteins Volatile Fatty Acids Wild Type Mouse base colon carcinogenesis colon microbiota differential expression dysbiosis functional status gene interaction gut microbiota in vivo malignant breast neoplasm microbial public health relevance transcriptome tumor

项目摘要

DESCRIPTION (provided by applicant): LC5A8 was first identified as a candidate tumor suppressor in colon. We showed that it is a Na+-coupled transporter for short-chain fatty acids (SCFAs) and that its ability to energize the cellular entry of the SCFA butyrate, a bacterial fermentation product of dietary fiber and an inhibitor of histone deacetylases, underlies its tumor-suppressive function in colon. However, in vivo studies with Slc5a8-/- mice failed to support such a function. Now we found that the ability of Slc5a8 to protect against colitis and colon cancer is dictated by dietary fiber content. The transporter is obligatory for the beneficial effects of SCFAs in colonic epithelial cells only when the luminal concentrations of SCFAs are low (low fiber intake). In contrast, the obligatory role of the transporter in mucosal immune cells is not dependent on dietary fiber content. We hypothesize that SLC5A8 is a conditional tumor suppressor in colon and is essential for the maintenance of the tolerogenic phenotype of the mucosal immune system, but the obligation of its role in colonic epithelial cells and LP immune cells is differentially influenced by the dietary fiber content. In addition, we hypothesize that SLC5A8 and optimal dietary fiber protect against bacterial dysbiosis in the gut, which is known to drive inflammation and cancer in colon. We will test these hypotheses by completing the following specific aims: (1A) Show that Slc5a8 is essential for the immunotolerant phenotype of the mucosal immune system by qualitatively and quantitatively increasing the number of anti- inflammatory dendritic cells and immunosuppressive Tregs in colon, and determine the relevance of dietary fiber content to this process; (1B) Delineate the phylogenetic profile of gut microbiota in wild type and Slc5a8-/- mice under low-fiber & high-fiber conditions to determine if bacterial dysbiosis occurs in the gut as a consequence of Slc5a8 deletion and/or low dietary fiber, thus driving the increased severity of colitis and enhanced colon cancer observed in Slc5a8-/- mice under low-fiber dietary conditions; (2A) Interrogate the contribution of Slc5a8 in colonic epithelial cells versus Slc5a8 in myeloid cells to the protection against experimental colitis under low-fiber & high-fiber dietary conditions using conditional knockout mice with selective deletion of Slc5a8 either in epithelial cells or in myeloid cells; (2B) Interrogate the contribution of Slc5a8 in colonic epithelial cells versus Slc5a8 in myeloid cells to the protection against experimental colon cancer under low-fiber & high-fiber dietary conditions using conditional knockout mice with selective deletion of Slc5a8 either in epithelial cells or in myeloi cells; (3) Dissect the changes in histone acetylation and consequent transcriptome landscape in colonic epithelial cells and LP dendritic cells that are responsible for the ability of Slc5a8 to protect against colitis and colon cancer under low-fiber & high-fiber dietary conditions.

描述（由申请人提供）：LC 5A 8首次被鉴定为结肠中的候选肿瘤抑制因子。我们发现，它是一个Na+耦合转运短链脂肪酸（SCFAs）和它的能力，激励进入细胞的SCFA丁酸酯，细菌发酵产物的膳食纤维和组蛋白脱乙酰酶的抑制剂，在结肠肿瘤抑制功能的基础。然而，用Slc 5a 8-/-小鼠进行的体内研究未能支持这种功能。现在我们发现Slc 5a 8预防结肠炎和结肠癌的能力取决于膳食纤维含量。运输商是有义务为有益的只有当SCFA的管腔浓度低（低纤维摄入）时，SCFA才能在结肠上皮细胞中发挥作用。相反，粘膜免疫细胞中转运蛋白的强制性作用不依赖于膳食纤维的含量。我们假设SLC 5A 8是结肠中的条件性肿瘤抑制因子，并且对于维持粘膜免疫系统的耐受性表型是必不可少的，但是其在结肠上皮细胞和LP免疫细胞中的作用的义务受到膳食纤维含量的差异影响。此外，我们假设SLC 5A 8和最佳膳食纤维可以防止肠道中的细菌生态失调，这是已知的结肠炎症和癌症。（1A）通过定性和定量地增加结肠中抗炎树突状细胞和免疫抑制性T细胞的数量来证明Slc 5a 8对于粘膜免疫系统的免疫耐受表型是必需的，并确定膳食纤维含量与该过程的相关性;（1B）描绘野生型和Slc 5a 8-/-小鼠在低纤维和高纤维条件下的肠道微生物群的系统发育谱，以确定肠道中是否由于Slc 5a 8缺失和/或低膳食纤维而发生细菌生态失调，从而导致在低纤维饮食条件下在Slc 5a 8-/-小鼠中观察到的结肠炎严重程度增加和结肠癌增强;（2A）询问结肠上皮细胞中的Slc 5a 8相对于骨髓细胞中的Slc 5a 8对在低纤维和高纤维条件下针对实验性结肠炎的保护的贡献。（2B）询问结肠上皮细胞中的Slc 5a 8相对于髓样细胞中的Slc 5a 8对保护结肠上皮细胞或髓样细胞中的Slc 5a 8的贡献在低纤维和高纤维饮食条件下使用在上皮细胞或骨髓细胞中选择性缺失Slc 5a 8的条件性敲除小鼠对抗实验性结肠癌;（3）解剖结肠上皮细胞和LP树突状细胞中组蛋白乙酰化和随之而来的转录组景观的变化，这些变化负责Slc 5a 8在低纤维和低浓度条件下保护结肠炎和结肠癌的能力。高纤维饮食条件。