Impact of HIV/SIV Infection on Paneth and Intestinal Stem Cell Interaction

HIV/SIV 感染对潘氏和肠道干细胞相互作用的影响

• 批准号: 9349058
• 负责人: Bapi Pahar
• 金额: $ 63.55万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-05 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349058
• 关键词: ALCAM gene; Abbreviations; Ablation; Acquired Immunodeficiency Syndrome; Acute; Adult; Animal Model; Anti-inflammatory; Apoptosis; Bacteria; Biopsy; CD4 Positive T Lymphocytes; CD44 gene; Cell Communication; Cell Compartmentation; Cell physiology; Cells; Chronic; Clonal Expansion; Coculture Techniques; Communication; Data; Development; EGF gene; Enterocytes; Enteroendocrine Cell; Epidermal Growth Factor; Epithelial; Epithelial Cells; Family; Fibrosis; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Genes; Genetic Transcription; Goblet Cells; HIV; HIV Enteropathy; HIV Infections; Homeostasis; Impairment; In Vitro; Individual; Infection; Inflammatory Response; Injury; Interferons; Interleukin-10; Intestines; LGR5 gene; Lead; Leucine-Rich Repeat; Ligands; Link; Lymphoid Tissue; Macaca; Macaca mulatta; Mediating; Modeling; Molecular; Mouse Mammary Tumor Virus; Natural regeneration; Paneth Cells; Pathogenesis; Pathology; Patients; Play; Positioning Attribute; Quantitative Reverse Transcriptase PCR; Recovery; Regulator Genes; Reserve Stem Cell; Role; Route; SIV; Secretory Cell; Signal Transduction; Site; Small Intestines; Stem cells; Structure of intestinal gland; Study models; Systems Biology; Testing; Tight Junctions; Tissues; Transforming Growth Factors; Villus; Virus Diseases; base; cell injury; cell type; differential expression; genetic analysis; human tissue; immune activation; integration site; interleukin-10 receptor; intestinal crypt; jejunum; microbial; nonhuman primate; notch protein; protein expression; repaired; selective expression; self renewing cell; stem cell division; stem cell population; transcriptome; transcriptomics

PROJECT SUMMARY Worldwide more than 90% of all HIV infections occur via mucosal route. The gastrointestinal tract is a site of massive CD4 T-cell depletion, viral infection, enterocyte apoptosis, disruption of epithelial tight junctions leading to microbial translocation, and lymphoid tissue fibrosis. The SIV infected rhesus macaque (RM) model is considered a well-accepted model to study of HIV-associated enteropathy and we have recently discovered that intestinal epithelial cell (iEC) apoptosis and diminished iEC regeneration occur soon after SIV-infection. Internalization of IL-10R with the resultant impact on IL-10 signaling and dysregulation of the IL-10-mediated anti-inflammatory responses also play a crucial role in iEC damage and subsequent SIV pathogenesis. Understanding the aberrant iEC regeneration in HIV/SIV might lead to an alternative approach for the treatment of HIV-mediated enteropathy based on enhancing iEC repair mechanisms. In the small intestine, each intestinal villus is encircled by at least six crypts of Lieberkühn, which house dedicated populations of stem and progenitor cells that self-renew, as well as give rise to the various differentiated iECs. LGR5+ (Leu- rich repeat containing G protein-coupled receptor 5) was identified as the marker for crypt base columnar (CBC) stem cells that was selectively expressed at the base of adult intestinal crypts. Genetic analysis of LGR5+ intestinal stem cells (ISCs) revealed that a single stem cell leads to crypt homeostasis in adult intestines by clonal expansion. Stem cells give rise to the polarized enterocytes, goblet cells, enteroendocrine cells, and tuft cells that migrate up to the villi after passing through several transiently-amplifying (TA) stages. TA cells also terminally differentiate into Paneth cells (PCs), a highly specialized secretory cell type which intersperse with stem cells at the base of the crypts in the small intestine. Recent cell ablation and co-culture studies showed that PCs provide essential niche signals to support LGR5+ stem cell renewal and survival. Therefore, we hypothesize that HIV/SIV infection disrupts the communication between LGR5+ ISC and PCs leading to diminished iECs regeneration. In Aim 1, we will define the correlates of LGR5+ stem cells and PCs with SIV/HIV infection status. In Aim 2, we will uncover the alterations of ISCs and PCs communication in SIV infection in two sub aims. In Sub-Aim 2a, we will determine the transcriptional programming of ISCs and PCs in normal and SIV infected RMs. In Sub-Aim 2b, we will compare the colony forming efficiency of rhesus intestinal LGR5+ stem cells between SIV infected and normal RMs.

项目摘要 全世界90%以上的HIV感染是通过粘膜途径发生的。胃肠道是一个部位， 大量CD 4 T细胞耗竭、病毒感染、肠上皮细胞凋亡、上皮紧密连接破坏 导致微生物移位和淋巴组织纤维化。SIV感染恒河猴（RM）模型 被认为是研究HIV相关肠病的公认模型，我们最近发现 肠上皮细胞（iEC）凋亡和减少iEC再生发生后不久，SIV感染。 IL-10 R的内化，从而影响IL-10信号传导和IL-10介导的免疫调节异常。 抗炎反应也在iEC损伤和随后的SIV发病机制中起关键作用。 了解HIV/SIV中异常的iEC再生可能会导致一种替代方法， 基于增强iEC修复机制治疗HIV介导的肠病。在小肠中， 每个肠绒毛被至少六个Lieberkühn隐窝包围，这些隐窝容纳了专门的 干细胞和祖细胞自我更新，并产生各种分化的iEC。LGR 5+（Leu- 富含重复序列的G蛋白偶联受体5）被鉴定为隐窝基底柱状的标志物 (CBC)选择性表达于成年肠腺基部的干细胞。的遗传分析 LGR 5+肠干细胞（ISCs）揭示了单个干细胞导致成年人隐窝内稳态 肠通过克隆扩张。干细胞产生极化的肠上皮细胞，杯状细胞，肠内分泌细胞， 细胞和簇状细胞，在经过几个瞬时扩增（TA）阶段后迁移到绒毛。 TA细胞还终末分化为潘氏细胞（PC），潘氏细胞是一种高度特化的分泌细胞类型， 在小肠的隐窝底部散布着干细胞。最近的细胞消融和共培养 研究表明，PC提供了支持LGR 5+干细胞更新和存活的基本生态位信号。 因此，我们假设HIV/SIV感染破坏了LGR 5 + ISC和LGR 5 + ISC之间的通讯。 PC导致IEC再生减少。在目标1中，我们将定义LGR 5+干细胞的相关性， 和SIV/HIV感染状态的PC。在目标2中，我们将揭示ISC和PC的变化 在SIV感染的两个子目标中的沟通。在子目标2a中，我们将确定 正常和SIV感染RM中ISC和PC的编程。在子目标2b中，我们将比较殖民地 恒河猴肠道LGR 5+干细胞在SIV感染和正常RM之间的形成效率。