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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）：LC5A8首先被鉴定为结肠中的候选肿瘤抑制因子。我们证明它是短链脂肪酸 (SCFA) 的 Na+ 偶联转运蛋白，并且它能够为 SCFA 丁酸盐（膳食纤维的细菌发酵产物和组蛋白脱乙酰酶抑制剂）进入细胞提供能量，这是其在结肠中抑制肿瘤功能的基础。然而，Slc5a8-/-小鼠的体内研究未能支持这种功能。现在我们发现 Slc5a8 预防结肠炎和结肠癌的能力取决于膳食纤维含量。运输者对受益人有义务仅当 SCFA 的管腔浓度较低（纤维摄入量低）时，SCFA 才会对结肠上皮细胞产生影响。相反，转运蛋白在粘膜免疫细胞中的必要作用不依赖于膳食纤维含量。我们假设 SLC5A8 是结肠中的条件性肿瘤抑制因子，对于维持粘膜免疫系统的耐受表型至关重要，但其在结肠上皮细胞和 LP 免疫细胞中的作用义务受到膳食纤维含量的不同影响。此外，我们假设 SLC5A8 和最佳膳食纤维可以防止肠道细菌失调，众所周知，细菌失调会导致结肠炎症和癌症。我们将通过完成以下具体目标来检验这些假设：（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Treg的数量，证明Slc5a8对于粘膜免疫系统的免疫耐受表型至关重要，并确定膳食纤维含量与这一过程的相关性； (1B) 描绘低纤维和高纤维条件下野生型和 Slc5a8-/- 小鼠肠道微生物群的系统发育谱，以确定肠道中是否因 Slc5a8 缺失和/或低膳食纤维而发生细菌失调，从而导致低纤维饮食下 Slc5a8-/- 小鼠中观察到的结肠炎严重程度增加和结肠癌增强状况; (2A) 使用选择性删除上皮细胞或骨髓细胞中的 Slc5a8 的条件敲除小鼠，探讨结肠上皮细胞中的 Slc5a8 与骨髓细胞中的 Slc5a8 对在低纤维和高纤维饮食条件下预防实验性结肠炎的贡献； (2B) 探讨结肠上皮细胞中的 Slc5a8 与骨髓细胞中的 Slc5a8 对保护的贡献使用条件敲除小鼠，在上皮细胞或骨髓细胞中选择性删除 Slc5a8，在低纤维和高纤维饮食条件下对抗实验性结肠癌； (3) 剖析结肠上皮细胞和 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 Slc5a8 在低纤维和高纤维饮食条件下预防结肠炎和结肠癌的能力。