Cell Fate Determination of Intestine/Chronic Diarrhea

肠道/慢性腹泻的细胞命运测定

• 批准号: 7080886
• 负责人: MARTIN G MARTIN
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080886
• 关键词: biotechnology; cell differentiation; cellular pathology; clinical research; congenital gastrointestinal disorder; diarrhea; endocrine gland /system; gastrointestinal epithelium; gel mobility shift assay; gene mutation; genetic screening; histopathology; human genetic material tag; human tissue; infant human (0-1 year); malabsorption; neurotrophic factors; transcription factor

DESCRIPTION (provided by applicant): Congenital diarrhea is an uncommon yet devastating clinical condition that frequently leads to intestinal failure. Many patients with chronic/congenital diarrhea of early infancy have defects in a variety of transporters and enzymes that have important roles in the process of nutrient and ion digestion and absorption. Presently, a large proportion of children with congenital diarrhea have a generalized malabsorptive form that has not been well characterized clinically, and its molecular basis has yet to be elucidated. Recent studies in null mice have determined that two basic-helix-loop-helix (bHLH) transcriptional factors, mouse atonal homolog 1 (MATH1) and neurogenin-3 (ngn-3) influence enteroendocrine, Paneth, goblet and epithelial cell fate determination. In the preliminary results section of this grant, we present for the first time the clinical characteristics and molecular basis of a novel human disorder that presented with severe congenital malabsorptive diarrhea. Histological evaluation of two cases revealed an absence of small and large bowel enteroendocrine cells, while the other intestinal cell types, including Paneth, goblet and absorptive cells were of normal appearance. Molecular analysis identified two homozygous mutations in neurogenin-3 that alter highly conserved amino acid residues in the DNA binding domain of the neurogenin gene family. In this grant, our central hypothesis is that abnormalities of enteroendocrine cell development, resulting from loss-of-function mutations of ngn-3 (or its upstream regulator HATH1) are a common yet currently unappreciated cause of chronic malabsorptive diarrhea during early infancy. Therefore, to test our central hypothesis, we propose to: [1] assess whether loss-of-function mutations of neurogenin-3 is frequently seen in children that present with chronic congenital malabsorptive diarrhea; [2] whether mutations of HATH1, the regulator of neurogenin-3, can be identified in a subset of cases that present with congenital diarrhea during early infancy. The long-term objective of this proposal is to assess whether abnormalities of small bowel cell fate determination in humans are associated with gastrointestinal symptoms and other potential clinical problems.

描述（由申请人提供）：先天性腹泻是一种罕见但具有破坏性的临床疾病，经常导致肠道衰竭。许多婴儿期早期慢性/先天性腹泻患者存在多种转运体和酶的缺陷，这些转运体和酶在营养物质和离子的消化吸收过程中起着重要作用。目前，很大比例的先天性腹泻患儿具有广泛性吸收不良形式，临床尚未很好地表征，其分子基础尚未阐明。最近对小鼠的研究发现，两个基本螺旋-环-螺旋（bHLH）转录因子，小鼠无性同源物1 （MATH1）和神经原素-3 （ngn-3）影响肠内分泌、Paneth、杯状和上皮细胞命运的决定。在本拨款的初步结果部分，我们首次提出了一种以严重先天性吸收不良腹泻为表现的新型人类疾病的临床特征和分子基础。2例组织学检查显示小肠和大肠肠内分泌细胞缺失，其他肠细胞类型包括Paneth、杯状细胞和吸收细胞外观正常。分子分析鉴定了神经原素-3的两个纯合突变，它们改变了神经原素基因家族DNA结合域中高度保守的氨基酸残基。在这项研究中，我们的中心假设是，由ngn-3（或其上游调节因子HATH1）的功能突变丧失引起的肠内分泌细胞发育异常是婴儿早期慢性吸收不良腹泻的常见原因，但目前尚未得到重视。因此，为了验证我们的中心假设，我们建议：[1]评估神经原素-3的功能丧失突变是否常见于患有慢性先天性吸收不良腹泻的儿童；是否可以在婴儿期早期出现先天性腹泻的一小部分病例中识别出神经原素-3的调节因子HATH1的突变。这项提议的长期目标是评估人类小肠细胞命运决定的异常是否与胃肠道症状和其他潜在的临床问题有关。