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Schlafen mediation of intestinal adaptation

施拉芬介导肠道适应

基本信息

批准号：
8542314
负责人：
MARC D. BASSON
金额：
$ 21.74万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8542314
关键词：
Adult Affect Animal Model Atrophic Biology Biopsy Butyrates Cell Differentiation process Cell Nucleus Cells Childhood Critical Illness Cytoplasm DNA Binding DNA-Binding Proteins Data Development Disease Epithelial Epithelial Cells Excision Failure Fasting Feedback Gastric Bypass Genetic Transcription Growth Factor Healed Homeobox Homeodomain Proteins Human Hypertrophy In Vitro Infection Intervention Intestinal Diseases Intestinal Mucosa Intestines Joints Knockout Mice Knowledge Lead Learning Lung Mediating Mediation Mediator of activation protein Molecular Chaperones Mucous Membrane Nuclear Operative Surgical Procedures Orthologous Gene Parenteral Nutrition Pathway interactions Patients Peptides Protein Family Proteins Qualifying Rattus Regulatory Pathway Rodent Rodent Model Running Sepsis Short Bowel Syndrome Site Small Intestines Somatotropin Starvation Stimulus Tetanus Helper Peptide Tissues Total Parenteral Nutrition Transplantation Viral Work base cell growth cell type healing improved in vivo insight meetings mortality novel nucleocytoplasmic transport nutrition overexpression prevent protein function response success

项目摘要

DESCRIPTION (provided by applicant): Mucosal atrophy often leads to barrier failure and sepsis in starving or fasting patients in spite of total parenteral nutrition (TPN). In addition, mny patients who undergo massive bowel resection fail to adapt and must be maintained on permanent TPN with high mortality. Current therapies aimed at preventing mucosal atrophy and enhancing adaptation are limited in efficacy, perhaps because they mostly induce proliferation. We propose that we must learn to promote differentiation as well as proliferation to achieve an intact functional mucosa, reverse mucosal atrophy, and engender maximal intestinal adaptation. Some Schlafen-family proteins mediate cell growth, differentiation, or development in some cells in a Schlafen- and cell-specific fashion. We have demonstrated that the rodent protein Schlafen-3 (Slfn3) is induced during and required for intestinal epithelial differentiation in response to various stimuli. Our data indicate that Slfn3 varies with mucosal atrophy and promotes differentiation in vivo and that Schlafen-12 (SLFN12) is its human ortholog. We hypothesize that Schlafen 3/12 induction represents a fundamental and essential common pathway for enterocytic differentiation that can be specifically targeted to promote differentiation and maintain the mucosa. We further propose that Schlafens 3/12 are chaperoned to the nucleus where they enhance differentiation by affecting transcription and by a Cdx2 homeobox protein- dependent positive feedback mechanism. We will study intestinal mucosa in patients fasting on TPN (atrophy) or after Roux-en-Y gastric bypass (hypertrophy), rat and human intestinal epithelial cells in vitro, a novel rodent model of in vivo intestinal epithelial atrophy and hypertrophy, in vivo viral Slfn3/SLFN12 infection, and a tet-inducible intestine-specific Slfn3 knock-out mouse to achieve the following specific aims: 1) show that SLFN12 mediates human enterocytic differentiation and mirrors Slfn3 changes with differentiation in mucosal atrophy or hypertophy, 2) determine the mechanism by which Slfn3 and SLFN12 promote differentiation in rat and human intestinal epithelial cells, and 3) demonstrate that manipulating Slfn3/SLFN12 or a nuclear chaperone modulates intestinal atrophy/adaptation in vivo. This study will fill a critica knowledge gap because we will delineate a fundamental mechanism by which diverse stimuli regulate intestinal epithelial differentiation. This may facilitate interventions to maintain the mucosal barrier in starving or critically ill patients with mucosal atrophy and promote nutrition i pediatric or adult short bowel syndrome. The Slfn3 knock-out mouse will provide valuable insights not only into the convergent differentiation regulatory pathway we will study but also int normal gut development, mucosal healing and other intestinal disorders such as IBD. In addition, understanding how Schlafen proteins promote differentiation will have broader implications for differentiation and development in other epithelial tissues.

描述（由申请方提供）：尽管接受全胃肠外营养（TPN），但饥饿或禁食患者的粘膜萎缩通常会导致屏障功能衰竭和败血症。此外，许多接受大面积肠切除术的患者不能适应，必须维持永久性TPN，死亡率高。目前旨在预防粘膜萎缩和增强适应性的疗法在功效上是有限的，可能是因为它们主要诱导增殖。我们建议，我们必须学会促进分化和增殖，以实现完整的功能性粘膜，逆转粘膜萎缩，并产生最大的肠道适应。一些Schlafen家族蛋白以Schlafen和细胞特异性方式介导某些细胞中的细胞生长、分化或发育。我们已经证明，啮齿类动物蛋白Schlafen-3（Slfn 3）的诱导过程中和所需的肠上皮细胞分化响应于各种刺激。我们的数据表明，SLFN 3随粘膜萎缩而变化，并促进体内分化，Schlafen-12（SLFN 12）是其人类直系同源物。我们假设Schlafen 3/12诱导代表了肠细胞分化的基本和必需的共同途径，可以特异性地靶向促进分化和维持粘膜。我们进一步提出Schlafens 3/12被陪伴到细胞核，在那里它们通过影响转录和Cdx 2同源框蛋白依赖性正反馈机制来增强分化。我们将研究禁食TPN（萎缩）或Roux-en-Y胃旁路术后患者的肠粘膜（肥大）、体外大鼠和人肠上皮细胞、体内肠上皮萎缩和肥大的新啮齿动物模型、体内病毒Slfn 3/SLFN 12感染和tet诱导的丝氨酸特异性Slfn 3敲除小鼠，以实现以下具体目的：1）显示SLFN 12介导人肠细胞分化并反映了Slfn 3在粘膜萎缩或肥大中的分化变化，2）确定了Slfn 3和SLFN 12促进大鼠和人肠上皮细胞分化的机制，和3）证明操纵Slfn 3/SLFN 12或核伴侣在体内调节肠萎缩/适应。这项研究将填补一个关键的知识空白，因为我们将描绘一个基本的机制，不同的刺激调节肠上皮分化。这可能有助于维持饥饿或危重粘膜萎缩患者的粘膜屏障的干预措施，并促进儿童或成人短肠综合征的营养。Slfn 3基因敲除小鼠将提供有价值的见解，不仅是我们将研究的趋同分化调控途径，而且是正常肠道发育，粘膜愈合和其他肠道疾病，如IBD。此外，了解Schlafen蛋白如何促进分化将对其他上皮组织的分化和发育产生更广泛的影响。

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）

The P-loop region of Schlafen 3 acts within the cytosol to induce differentiation of human Caco-2 intestinal epithelial cells.

DOI：
10.1016/j.bbamcr.2014.09.017
发表时间：
2014-12
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Chaturvedi L;Sun K;Walsh MF;Kuhn LA;Basson MD
通讯作者：
Basson MD

Schlafen 3 Mediates the Differentiating Effects of Cdx2 in Rat IEC-Cdx2L1 Enterocytes.

DOI：
10.3109/08941939.2015.1005780
发表时间：
2015
期刊：
Journal of investigative surgery : the official journal of the Academy of Surgical Research
影响因子：
0
作者：
Walsh MF;Hermann R;Lee JH;Chaturvedi L;Basson MD
通讯作者：
Basson MD

Schlafen 12 expression modulates prostate cancer cell differentiation.