Characterization of intestinal regeneration in a model of intestinal atresia

描述（由申请人提供）：在本提案中，我们使用先天性人类缺陷的遗传小鼠模型来研究胚胎肠内以前未知的再生机制。先天性缺陷是一种肠闭锁，它在产前形成，并导致部分肠管的节段性缺失。闭锁新生儿时期出现的一种肠梗阻。很大比例的肠闭锁患者会出现短肠综合征/肠衰竭（SGS/IF），这是一种肠道缺乏足够的长度和表面积来吸收足够的热量以满足营养需求的情况。目前，SGS/IF的治疗选择是有限的，适用于这些患者的一部分。本研究将探索胚胎肠的再生潜能。这一点很重要，因为目前还没有治疗方法能够使我们实现利用患者自身细胞替代SGS/IF患者肠道的长期目标。这项研究具有创新性，因为它开辟了两种范式转变的可能性。第一种可能性是我们实验室认识到胚胎肠在损伤后具有再生的潜力。第二种可能性是再生需要一个来自于

DESCRIPTION (provided by applicant): In this proposal we use a genetic mouse model of a congenital human defect to study a previously unknown regenerative mechanism within the embryonic intestine. The congenital defect is an intestinal atresia which forms prenatally and results in a segmental absence of a portion of the intestinal tube. Atresias present in the newborn period as an intestinal obstruction. A significant percentage of patients with intestinal atresia develop shortgut syndrome/Intestinal failure (SGS/IF), a condition where the intestine lacks sufficient length and surface area to absorb adequate calories in order to meet nutritional requirements. Currently, the therapeutic options for SGS/IF are limited and applicable to a subset of these patients. The proposed research will explore the regenerative potential of the embryonic intestine. This is significant because there are no therapies that enable us achieve our long-range goal of utilizing the patient's own cells to replace intestine in SGS/IF. This research is innovative because it has opened up the possibility of two paradigm shifts. The first possibility is the recognition by our laboratory that the embryonic intestine has the potential to regenerate after injury. The second possibility is that regeneration requires a cell derived from a one germ layer (mesoderm) to transdifferentiate and function as a cell type normally derived from a separate germ layer (endoderm): a process also known as lineage reprogramming. Aim 1 will test the hypothesis that the endoderm compartment is invaded by a lateral plate mesoderm derived lineage of cells during the post-apoptotic phase of atresia formation. Aim 2 will test whether the invading cells are capable of fully transdifferentiating and assuming an endodermal fate following invasion. These hypotheses were formulated out of preliminary data from my laboratory. The expected results will illuminate a novel regenerative mechanism that enables the intestine to reconstitute the endoderm compartment and rescue development after injury. Expected results will open up an entirely new line of investigation in a previously unknown area of intestinal development. Furthermore, they will be the next steps towards exploiting this response to realize our very long-term goal of developing regenerative therapies for patients with SGS/IF: a disease that afflicts over 20,000 patients (NIH- PA-06-230) in this country.