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Intestinal Smooth Muscle Phenotypic Class Switching in Myopathic Pediatric Intestinal Pseudo-obstruction

Award Number: K08DK149313
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Intestinal Smooth Muscle Phenotypic Class Switching in Myopathic Pediatric Intestinal Pseudo-obstruction - Project Summary/Abstract Myopathic pediatric intestinal pseudo-obstruction (mPIPO) is a rare, life-threatening disorder characterized by profound bowel muscle weakness, causing massive abdominal distension, vomiting, and severe constipation, with 55% mortality by age 20. Most cases result from mutations in smooth muscle contractile genes, particularly ACTG2. Children with mPIPO experience puzzling fluctuations in disease severity, with seemingly minor infections triggering weeks to months of complete intestinal failure requiring intravenous nutrition. The central hypothesis of this research is that phenotypic switching—a reversible process where contractile smooth muscle cells convert to pro-fibrotic, weakly contractile synthetic cells—drives these symptom fluctuations through a two-hit mechanism: pathogenic ACTG2 mutations create baseline dysfunction while inflammatory mediators like TNFα trigger additional switching via NFκB activation, leading to progressive loss of contractile function. Specific Aim 1 will define molecular mechanisms underlying inflammation-induced phenotypic switching in human intestinal smooth muscle cells (HISMC). Preliminary RNA sequencing data demonstrate that TNFα dramatically alters HISMC gene expression, increasing synthetic markers and matrix metalloproteinases while decreasing contractile genes. These studies will employ advanced culture techniques, including serum-free muscularis medium and aligned nanofibrous scaffolds, to maintain mature contractile phenotypes. Fourier Transform Traction Microscopy will quantify single-cell contractility changes following TNFα exposure. Subsequent experiments will test whether NFκB inhibition using FDA-approved tacrolimus and genetic knockdown prevents or reverses TNFα-induced phenotypic switching, establishing proof-of-concept for translational therapies. Specific Aim 2 will determine whether the mPIPO-causing ACTG2 R257C mutation promotes phenotypic switching using induced pluripotent stem cell (iPSC)-derived human intestinal organoids grown via a Confined Culture System that generates centimeters of full-thickness, functional human bowel. Organ bath contractility studies, histology, and electron microscopy will characterize muscle function in mutant versus corrected isogenic organoids. Xenium spatial transcriptomics will profile gene expression in archived human intestinal tissue from mPIPO patients, neuropathic pseudo-obstruction controls, and healthy subjects, validated by RNAScope in situ hybridization. These studies will generate the first comprehensive human mPIPO model systems, test whether FDA- approved NFκB inhibitors could prevent disease flares, and provide foundational knowledge about smooth muscle phenotypic plasticity in visceral myopathy. This work positions Dr. Wolfson to pursue an independent physician-scientist career developing novel therapeutics for this devastating pediatric disease.


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: 2026 ( Subtotal = $160,056 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/19/2026	NEW	$160,056
														Subtotal = $160,056

Grand Total All Awards = $160,056

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Intestinal Smooth Muscle Phenotypic Class Switching in Myopathic Pediatric Intestinal Pseudo-obstruction

Award Number: K08DK149313

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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