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Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease

Award Number: DP1DK130660
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease - ABSTRACT Protein-losing enteropathy (PLE) is the term given to the pathological phenomenon of protein dumping from the systemic circulation into the intestinal lumen. Various degrees of PLE are observed in a variety of otherwise unrelated diseases. For instance, PLE is a complication of the life-saving Fontan palliation procedure performed on children born with only a single ventricle of the heart to create a vascular diversion to the lungs to promote improved oxygenation of blood. Fontan-associated PLE is linked with high mortality: 30-50% over 5- to 10-years. Yet, PLE remains understudied. The dominant causal mechanisms underlying PLE appear to relate to (1) loss of barrier integrity at the intestinal epithelium or (2) functional disturbance of the lymphatic vasculature. Intestinal epithelial cell erosion would expose proteinaceous tissue fluid to the intestinal lumen. Furthermore, poor epithelial intercellular junctions might allow for the contents of the lamina propria interstitium to leak into the intestinal lumen. With respect to lymphatics, failure of lymph to flow away from the intestine uni-directionally toward the heart and instead to flow backwards from the body trunk toward the intestine with sufficient force to break across the epithelium may be a major cause of PLE. The literature presents Fontan palliation-associated PLE as a problem driven by lymphatic backflow, whereas PLE in IBD (such as Crohn's disease) is presented as being of mixed etiology that involves breach of epithelial integrity with possible additional contributions stemming from lymphatic dysfunction. However, it is acknowledged in the literature that the full basis of PLE in any of these conditions is uncertain and that there are several reasons why the current explanations may be questioned. We will carry out focused research on PLE that includes studies involving human participants as well as studies in experimental animal models. Our hypotheses are, first, that the lymphatic vasculature is a primary player in PLE affecting Fontan patients and IBD patients, and second, that the lymphatic vasculature must receive “two hits” to drive sufficient backflow of lymph to cause outflow from the intestinal barrier. The first of these hits has already been considered (but not completely tested) in the context of Fontan palliation: increased pressure within the chain of lymphangions (vessel units between lymphatic valves). We propose this second hit is an inflammatory signal that negatively affects lymphatic valves. The two-hit model may resolve a confusing observation in Fontan patients with PLE wherein treatments with steroids like budesonide can be effective. A steroid seems unlikely to strongly alter pressure in the venous and lymphatic systems, but it is easy to envision how steroids may help by reducing adverse inflammatory signalling associated with valve failure. If this model is correct, a path to therapies not previously considered to treat PLE may become evident.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $716,331 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/1/2024	NON-COMPETING CONTINUATION	$716,331
														Subtotal = $716,331

Issue Date FY: 2023 ( Subtotal = $746,178 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/7/2023	NON-COMPETING CONTINUATION	$746,178
														Subtotal = $746,178

Issue Date FY: 2022 ( Subtotal = $771,525 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/7/2022	NON-COMPETING CONTINUATION	$771,525
														Subtotal = $771,525

Issue Date FY: 2021 ( Subtotal = $787,500 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/22/2021	NEW	$787,500
														Subtotal = $787,500

Grand Total All Awards = $3,021,534

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Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease

Award Number: DP1DK130660

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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