Interstitial cells of Cajal in diabetic gastropathy

糖尿病胃病中的卡哈尔间质细胞

• 批准号: 8892163
• 负责人: Tamas Ordog
• 金额: $ 34.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892163
• 关键词: Adult; Aging; Biological; Cell Maintenance; Cell Proliferation; Cells; Clinical Trials; Complex; Development; Diabetes Mellitus; Diabetic mouse; Disease; Disease model; Effectiveness; Enteral; Epigenetic Process; Feedback; Flow Cytometry; Gastrointestinal Motility; Gastroparesis; Genetic Transcription; Glycogen Synthase Kinase 3; Goals; Healthcare; Histones; Human; Interstitial Cell of Cajal; Intervention; Intrinsic factor; KITLG gene; Label; Laboratories; Lysine; Maintenance; Malignant Neoplasms; Mediating; Modality; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Muscle; Natural regeneration; Neurons; Nuclear; Organ; Oxidative Stress; Pathway interactions; Patients; Phosphorylation; Play; Polycomb; Preclinical Testing; Process; Production; Proteins; Receptor Protein-Tyrosine Kinases; Recombinant DNA; Repression; Residual state; Role; Signal Transduction; Smooth Muscle Myocytes; Staging; Stem Cell Factor; Stem cell transplant; Stem cells; Stomach; Symptoms; TCF Transcription Factor; Techniques; Testing; Therapeutic; Tissues; Transplantation; Transplanted tissue; Work; base; care burden; cell motility; cell type; diabetic; diabetic gastroparesis; gastrointestinal; histone methyltransferase; in vivo; inhibitor/antagonist; motility disorder; mouse model; neuromuscular; new technology; nodal myocyte; novel; novel strategies; postnatal; pre-clinical; preclinical study; repaired; self-renewal; small molecule; stem cell differentiation; stem cell division; stem cell population; tool; transcription factor

DESCRIPTION (provided by applicant): Somatic stem cells residing in many organs are responsible for tissue maintenance and repair and also contribute to aging and cancer. While the role of stem cells and cell turnover is obvious in rapidly renewing tissues, their significance in the gastrointestinal neuromuscular compartment has only recently been recognized. The classic view of gastrointestinal motility disorders including diabetic gastroparesis is that they are due to impaired tissue function and degeneration of terminally differentiated cell types such as enteric neurons, smooth muscle cells and interstitial cells of Cajal (ICC). This is also reflected in current treatment modalities, which focus on symptom control and stimulation of residual function. However, these treatments are not curative and to a large extent ineffective. Recent studies demonstrating considerable plasticity of postnatal enteric neurons, smooth muscle cells and ICC indicate that this old view is untenable. We recently identified a stem cell residing in the gastric musculature of adult mice that can give rise to ICC (ICC-SC). This paradigm shift has opened entirely new opportunities to unravel the mechanisms of ICC maintenance and differentiation and to develop new, rational therapies to regenerate ICC networks from endogenous or transplanted tissue stem cells in these disorders. However, there are several barriers that must be overcome before this goal can be realized including a lack of understanding of the mechanisms that control ICC-SC self- renewal and differentiation, as well as the role of the tissue microenvironment in these processes. Therefore, the overall goals of the current project are to determine the key cell-intrinsic and cell-extrinsic factors that control ICC-SC proliferation and differentiation and to test pharmacological agents that target ICC-SC via these factors in preclinical disease models. Our first specific aim is to determine the role and mechanisms-of-action of polycomb group proteins as cell-intrinsic factors in the epigenetic control of ICC-SC maintenance and differentiation and to test the in vivo utility of indirect histone methyltransferase inhibitors to stimulate, through the inhibition of polycomb activity, the differentiation of transplanted and endogenous ICC-SC. Our second specific aim is to determine the role and molecular mechanisms-of-action of glycogen synthase kinase 3 (Gsk3) as an extrinsic factor in regulating ICC-SC through stem cell factor expression in smooth muscle cells and to determine the in vivo utility of Gsk3 inhibitors to reverse gastroparesis by supporting ICC-SC self- renewal and differentiation. We will use novel models and new technology developed in our laboratory including freshly isolated and cultured ICC-SC, transplantation of genetically labeled ICC-SC, and quantitative analysis of key stages of ICC development by flow cytometry. We will also employ state-of-the-art molecular biological and recombinant DNA techniques to study epigenetic control of gene transcription and mouse models for preclinical testing. The proposed studies will determine the mechanistic basis for, and set the stage for clinical trials of, novel pharmacological interventions for loss of ICC in motility diseases.

描述(申请人提供)：躯体干细胞存在于许多器官中，负责组织的维护和修复，也有助于衰老和癌症。虽然干细胞和细胞周转在快速更新的组织中的作用是显而易见的，但它们在胃肠道神经肌肉间隔中的重要性直到最近才被认识到。包括糖尿病胃轻瘫在内的胃肠动力障碍的经典观点是由于组织功能受损和终末分化细胞类型的退化，如肠系膜神经元、平滑肌细胞和Cajal间质细胞(ICC)。这也反映在目前的治疗方式上，这些治疗方式侧重于症状控制和刺激残留功能。然而，这些治疗方法并不能治愈，而且在很大程度上无效。最近的研究表明，出生后肠神经、平滑肌细胞和ICC具有相当大的可塑性，这一古老的观点是站不住脚的。我们最近发现了一种存在于成年小鼠胃肌肉中的干细胞，可以产生ICC(ICC-SC)。这种范式的转变为揭示ICC的维持和分化机制以及开发新的、合理的治疗方法以从这些疾病的内源性或移植组织干细胞再生ICC网络开辟了全新的机会。然而，在实现这一目标之前必须克服几个障碍，包括对控制ICC-SC自我更新和分化的机制以及组织微环境在这些过程中的作用缺乏了解。因此，本项目的总体目标是确定控制ICC-SC增殖和分化的关键细胞内和细胞外因素，并在临床前疾病模型中测试通过这些因素靶向ICC-SC的药理药物。我们的第一个特定目的是确定多梳状蛋白作为细胞内在因子在ICC-SC维持和分化的表观遗传学控制中的作用和作用机制，并测试间接组蛋白甲基转移酶抑制剂在体内的效用，通过抑制多梳状活性来刺激移植的和内源性ICC-SC的分化。我们的第二个特定目标是确定糖原合成酶激酶3(GSK3)作为外在因子通过干细胞因子在平滑肌细胞中的表达来调节ICC-SC的作用和分子机制，并确定GSK3抑制剂通过支持ICC-SC的自我更新和分化来逆转胃轻瘫的体内效用。我们将使用我们实验室开发的新模型和新技术，包括新鲜分离和培养的ICC-SC，基因标记的ICC-SC的移植，以及利用流式细胞仪对ICC发育的关键阶段进行定量分析。我们还将使用最先进的分子生物学和重组DNA技术来研究基因转录的表观遗传控制，以及用于临床前测试的小鼠模型。拟议的研究将确定运动性疾病中ICC丢失的新的药物干预的机制基础，并为临床试验奠定基础。