Cell Fate Determination of Intestine/Chronic Diarrhea

描述（由申请人提供）：先天性腹泻是一种罕见但破坏性的临床疾病，经常导致肠功能衰竭。许多患有早期婴儿慢性/先天性腹泻的患者存在多种转运蛋白和酶的缺陷，这些转运蛋白和酶在营养和离子消化和吸收过程中具有重要作用。目前，很大一部分先天性腹泻儿童具有广泛的吸收不良形式，临床上尚未得到很好的表征，其分子基础尚未阐明。最近的研究在无效小鼠已经确定，两个基本螺旋环螺旋（bHLH）转录因子，小鼠无调同源物1（MATH 1）和神经原蛋白-3（ngn-3）影响肠内分泌，潘氏，杯状和上皮细胞的命运决定。在本基金的初步结果部分，我们首次介绍了一种新型人类疾病的临床特征和分子基础，这种疾病表现为严重的先天性吸收不良性腹泻。2例组织学检查显示小肠和大肠肠内分泌细胞缺失，而其他肠细胞类型，包括潘氏细胞、杯状细胞和吸收细胞外观正常。分子分析确定了两个纯合突变的neurogenin-3，改变高度保守的氨基酸残基的DNA结合域的neurogenin基因家族。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HATH 1）的功能丧失突变引起的肠内分泌细胞发育异常是婴儿早期慢性吸收不良性腹泻的常见但目前未被认识的原因。因此，为了验证我们的中心假设，我们建议：[1]评估神经生成素-3的功能丧失突变是否经常出现在患有慢性先天性吸收不良性腹泻的儿童中; [2]是否可以在婴儿早期先天性腹泻的病例子集中鉴定神经生成素-3的调节因子HATH 1的突变。该提案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相关。

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.