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.
The proposed research is relevant to human health because it will identify a previously unrecognized mechanism of regeneration within the intestine that could potentially be activated to stimulate growth of intestine in patients who lack sufficient intestinal length to absorb calories and nutrients: a condition known as shortgut syndrome/intestinal failure. The life burden and cost of this disease for these patients and their families is extraordinary. The proposed research is therefore relevant to the NIH's mission: To seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability.
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