Human enteric nervous system progenitor dynamics during development and disease

人类肠神经系统祖细胞在发育和疾病过程中的动态

• 批准号: MR/Y013476/1
• 负责人: Anestis Tsakiridis
• 金额: $ 137.68万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013476%2F1
• 关键词: Human; enteric; nervous; system; progenitor

The proper function of our gut is controlled, in an involuntary fashion, by a complex network of nerves, the enteric nervous system (ENS), also known as the 'second brain'. The ENS is produced in utero by specialised cell populations known as ENS progenitors and Schwann cell precursors (SCPs). Mistakes in the generation of the ENS by these progenitors, often due to defects in our DNA (mutations), lead to birth conditions called enteric neuropathies that are marked by lack of nerves in the gut. The most common enteric neuropathy is Hirschsprung disease, which is a life-threatening intestinal disorder affecting approximately 1 in 5,000 newborn children. The lack of enteric nerves in Hirschsprung disease is usually caused by mutations in a gene called RET, which is important for the proper function of ENS progenitors. Strikingly, RET mutations do not seem to affect SCPs, the other complementary source of ENS cells. To better understand the causes of HSCR, it is therefore important to examine how ENS progenitors/SCPs produce enteric nerves and how RET mutations affect this process. To address this issue, we propose to use human stem cells to generate healthy and RET-mutant ENS progenitors and SCPs, and kept in culture in a petri dish. We will then study in detail the behaviour of the RET-mutant cell populations after their injection in gut tissue isolated from human patients and mice, and grown in the petri dish. Comparison of mutant and healthy cells will help us understand what goes wrong in Hirschsprung disease and will ultimately assist the development of therapies against this devastating childhood disease.

我们肠道的正常功能是由复杂的神经网络（肠神经系统（ENS），也称为“第二大脑”）以不自觉的方式控制的。 ENS 由称为 ENS 祖细胞和雪旺细胞前体 (SCP) 的特殊细胞群在子宫内产生。这些祖细胞在生成 ENS 时出现的错误，通常是由于我们的 DNA 缺陷（突变）造成的，会导致称为肠神经病的出生病症，其特征是肠道中缺乏神经。最常见的肠神经病是先天性巨结肠症，这是一种危及生命的肠道疾病，影响大约五千分之一的新生儿。先天性巨结肠症中肠神经的缺乏通常是由 RET 基因突变引起的，该基因对于 ENS 祖细胞的正常功能很重要。引人注目的是，RET 突变似乎并不影响 ENS 细胞的另一个补充来源 SCP。因此，为了更好地了解 HSCR 的原因，研究 ENS 祖细胞/SCP 如何产生肠神经以及 RET 突变如何影响这一过程非常重要。为了解决这个问题，我们建议使用人类干细胞来产生健康和 RET 突变的 ENS 祖细胞和 SCP，并保存在培养皿中培养。然后，我们将详细研究 RET 突变细胞群注射到从人类患者和小鼠身上分离出来并在培养皿中生长的肠道组织后的行为。突变细胞和健康细胞的比较将帮助我们了解先天性巨结肠症的问题所在，并最终有助于开发针对这种毁灭性儿童疾病的疗法。