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Dr. Colleen Nofi - Best of the Best in Pediatric Surgery 2025

Video Published 2025-03-19 Updated 2026-08-01

Timestops (5)

Introduction and Background on NEC

CIRP Biology and MOP3 Peptide Development

Experimental Model and Histological Findings

Barrier Function and Survival Outcomes

Discussion and Treatment Timing Questions

Topic Overview

Dr. Colleen Nofi presents research on extracellular cold-inducible RNA binding protein (eCIRP) in necrotizing enterocolitis (NEC). Using a murine NEC model, the study demonstrates that CIRP knockout mice show reduced NEC severity, decreased intestinal inflammation (IL-6, TNF-alpha), preserved intestinal barrier function, and 100% survival versus 65% in wild-type mice. A novel scavenging peptide (MOP3) reduced circulating eCIRP, decreased systemic and intestinal inflammation, protected intestinal barrier integrity, and improved survival to 80% versus 50% in vehicle-treated controls. The work establishes eCIRP as a therapeutic target in experimental NEC.

Key Takeaways

Extracellular CIRP (eCIRP) exacerbates NEC pathogenesis by amplifying inflammation and intestinal injury in preclinical models.
CIRP knockout mice showed 100% survival vs 65% in wild-type mice, demonstrating critical role of eCIRP in NEC mortality.
Novel peptide MOP3 scavenges eCIRP from circulation, reducing systemic inflammation (IL-6, TNF-α) and preserving intestinal barrier.
MOP3 treatment improved survival to 80% vs 50% vehicle control and reduced NEC severity scores in murine models.
Therapeutic targeting of eCIRP represents promising novel approach for NEC treatment where current options remain limited.

Inside this episode

Kai, the Library's AI content creator, listened to this episode and mapped who's speaking, the chapters, key claims, and cases. Every item links to the exact moment in the recording.

AI-enriched

Who's speaking

Speaker 1 — host
Colleen Nofi — guest
Colleen Nofi — guest
Speaker 4 — guest
Speaker 5 — guest

Chapters

0:00Introduction and Background on eCIRP in NEC — Introduction of presenter and research topic. Background on NEC pathophysiology, CIRP biology, and the development of MOP3 peptide as an eCIRP scavenger.
2:05CIRP Knockout Results in Murine NEC Model — Presentation of experimental design and results from CIRP knockout mice showing reduced NEC severity, decreased intestinal inflammation, preserved barrier function, and 100% survival.
4:10MOP3 Therapeutic Intervention Results — Results of MOP3 treatment showing reduced circulating eCIRP, decreased systemic and intestinal inflammation, preserved intestinal barrier, and improved survival to 80%.
5:42Conclusions and Q&A — Summary of findings and discussion of next steps including optimization of MOP3 delivery routes, validation in additional models, and maximizing therapeutic benefit.

Key claims

0:39Necrotizing enterocolitis is a devastating gastrointestinal disease impacting premature infants whose pathophysiology is driven by complex pathways that are not completely understood — Colleen Nofi
0:52NEC has limited treatment options and unacceptably high morbidity and mortality risk — Colleen Nofi
1:06Under biologic conditions, CIRP is found inside the cell where it acts as an RNA chaperone protein — Colleen Nofi
1:12In states of cellular stress such as sepsis, CIRP escapes outside the cell — Colleen Nofi
1:19Extracellular CIRP acts as a DAMP by enhancing the release of cytokines and chemokines and amplifying the inflammatory cascade — Colleen Nofi
1:33MOP3 (MFG-E8 derived oligopeptide 3) is an eCIRP scavenging peptide that removes eCIRP from circulation to reduce inflammation — Colleen Nofi
2:30CIRP knockout protected pups from NEC severity with preservation of intestinal villi architecture — Colleen Nofi
2:59CIRP knockout mice subjected to NEC showed reduced intestinal inflammation as measured by mRNA levels of IL-6 and TNF-alpha in the small bowel — Colleen Nofi
3:36CIRP knockout pups had reduced fluorescence intensity of enterically administered fluorescent dextran in serum, indicating preserved intestinal barrier function — Colleen Nofi
3:57CIRP knockout pups subjected to NEC had 100% survival compared to 65% survival in wild-type pups under the same model conditions — Colleen Nofi
4:18MOP3 treatment reduced circulating eCIRP levels in NEC pups compared to vehicle — Colleen Nofi
4:27Reduction in eCIRP with MOP3 treatment correlated with reduction in systemic inflammatory markers including IL-6 and TNF-alpha — Colleen Nofi
4:37MOP3 treatment protected against NEC severity with preservation of intestinal villi — Colleen Nofi
4:55MOP3 treatment reduced intestinal inflammation in NEC as measured by mRNA levels of IL-6 and TNF-alpha — Colleen Nofi
5:05MOP3 treated pups had significantly reduced fluorescence intensity of enterically administered dextran, indicating protection of intestinal barrier — Colleen Nofi
5:22Pups treated with MOP3 had 80% survival compared to 50% survival in vehicle-treated pups in the NEC model — Colleen Nofi
5:42eCIRP exacerbates NEC pathogenesis by increasing inflammation and intestinal injury — Colleen Nofi
5:42MOP3 protects against NEC pathogenesis by scavenging eCIRP and preventing deleterious downstream impacts — Colleen Nofi
6:53MOP3 is effective in other models of ischemia reperfusion injury in the gut — Colleen Nofi
7:00The beneficial impact of CIRP knockdown is greater than the benefit achieved with MOP3 treatment — Colleen Nofi
7:34The murine NEC model involves 4 days of continuous stressors including LPS, formula gavage, and hypoxia — Colleen Nofi
7:49MOP3 treatment is administered once per day at the beginning of the NEC model, ongoing with the insult — Colleen Nofi
6:38No single model of NEC fully recapitulates everything exhibited in neonates — Colleen Nofi

Open questions

What are the optimal routes of administration for MOP3 (including enteral delivery)?
How can the therapeutic benefit of MOP3 be maximized to approach the level of protection seen with complete CIRP knockout?
What is the translational pathway to bring MOP3 from murine models to clinical use in human neonates?

This episode was analyzed and enriched by Kai, the Library's AI content creator. Every item links to the moment it comes from — click a timestamp to listen in context.

Targeting Extracellular CIRP to Prevent Necrotizing Enterocolitis in Premature Infants

The episode's main topic retold as a plain-language walkthrough — what it is, why it matters, and what the speakers concluded. Written by Kai from the episode transcript and reviewed before publishing.

For the care team · Explainer · AI-written, human-reviewed

Why This Matters

Necrotizing enterocolitis remains one of the most feared complications in neonatal intensive care. Despite decades of research, treatment options remain limited to supportive care and surgical resection of necrotic bowel, and mortality remains unacceptably high 0:52. The disease arises from incompletely understood pathways involving intestinal immaturity, microbial colonization, and inflammatory amplification 0:39. This work identifies a specific molecular target—extracellular cold-inducible RNA-binding protein—that drives the inflammatory cascade in NEC and demonstrates that blocking it substantially reduces disease severity and mortality in experimental models.

The Core Problem

Under normal conditions, CIRP functions as an intracellular RNA chaperone protein 1:06. In states of cellular stress such as sepsis, CIRP escapes the cell and enters the extracellular space 1:12. Once outside, extracellular CIRP (eCIRP) acts as a damage-associated molecular pattern by enhancing cytokine and chemokine release and amplifying the inflammatory cascade 1:19. This transforms a housekeeping protein into an inflammatory amplifier. The hypothesis tested here is that eCIRP exacerbates NEC pathogenesis by increasing inflammation and intestinal injury 5:42.

How the Approach Works

The research employed two complementary strategies: genetic elimination of CIRP and pharmacologic scavenging of eCIRP using a novel peptide called MOP3 (MFG-E8 derived oligopeptide 3), which removes eCIRP from circulation 1:33.

In the genetic knockout experiments, CIRP-deficient pups subjected to experimental NEC showed preserved intestinal villi architecture and reduced histologic severity scores 2:30. Intestinal inflammation, measured by IL-6 and TNF-alpha mRNA levels in small bowel tissue, was markedly reduced 2:59. Functional barrier integrity—assessed by measuring systemic appearance of enterically administered fluorescent dextran—was preserved in knockout animals, indicating the intestinal wall remained intact 3:36. Most strikingly, CIRP knockout pups achieved 100% survival in the NEC model, compared to 65% survival in wild-type controls under identical conditions 3:57.

The therapeutic experiments using MOP3 recapitulated these findings. MOP3 treatment reduced circulating eCIRP levels 4:18, which correlated with reduced systemic IL-6 and TNF-alpha 4:27. Histologically, MOP3 preserved intestinal villi 4:37 and reduced intestinal inflammatory markers 4:55. Barrier function was protected, with significantly reduced systemic fluorescent dextran in treated animals 5:05. Survival improved to 80% with MOP3 treatment versus 50% in vehicle-treated controls 5:22.

The experimental model involves four days of continuous stressors including LPS, formula gavage, and hypoxia 7:34. MOP3 is administered once daily beginning at model initiation, running concurrently with the insult 7:49. This dosing strategy tests whether the peptide can prevent disease progression rather than simply rescue established injury.

Where Uncertainty Remains

The benefit achieved with complete CIRP knockout exceeds that achieved with MOP3 treatment 7:00. This gap suggests either incomplete eCIRP scavenging by the current peptide formulation or that intracellular CIRP depletion provides additional protective mechanisms beyond blocking extracellular signaling. Optimization of MOP3 delivery routes and dosing frequency may close this gap.

No single murine model fully recapitulates the clinical disease seen in human neonates 6:38. The four-day multi-hit model used here incorporates several known NEC triggers but cannot reproduce the complex interplay of prematurity, enteral feeding advancement, microbial dysbiosis, and individual patient vulnerability that characterizes human disease. The investigators are validating MOP3 efficacy in additional models of intestinal ischemia-reperfusion injury 6:53, which strengthens confidence in the mechanism but does not eliminate the translational gap.

The peptide has been administered systemically in these experiments. Whether enteral administration—more practical in neonates—would achieve sufficient mucosal or systemic drug levels remains unknown.

When to Think About This

This work does not yet inform clinical practice—MOP3 remains an investigational agent in preclinical development. For clinicians managing at-risk neonates, the relevant insight is mechanistic: eCIRP represents a potentially druggable node in the inflammatory amplification that drives NEC. If this pathway proves targetable in humans, it would represent the first disease-modifying therapy beyond supportive care.

The magnitude of the survival benefit—from 50% to 80% in the therapeutic model, and to 100% with complete CIRP elimination—is substantial enough to warrant continued translational development. The next steps involve optimizing delivery, validating across additional models, and ultimately moving toward early-phase human trials in high-risk neonates. For now, this remains a promising target in a disease that desperately needs one.

Takeaways from this story

Complete CIRP knockout achieved 100% survival vs 65% in controls; MOP3 treatment improved survival to 80% vs 50%
eCIRP acts as a DAMP, amplifying inflammation; blocking it preserves intestinal barrier and reduces cytokine release
MOP3 benefit lags behind genetic knockout, suggesting room for optimization of peptide delivery or dosing
The four-day murine model uses continuous stressors (LPS, formula, hypoxia) with daily MOP3 dosing from onset

Keywords

necrotizing enterocolitis NEC sepsis ischemia reperfusion injury formula gavage hypoxic stress fluorescent dextran administration MOP3 MFG-E8 derived oligopeptide 3 LPS lipopolysaccharide Cohen Children's Medical Center Northwell Health

Hashtags

#pediatricsurgery #necrotizingenterocolitis #NEC #CIRP #Mop3 #infanthealth #pediatricresearch #NeonatalSurgery #TranslationalMedicine

Transcript

All right. We're gonna go on to the uh next one. this is now ABSA, and it is, uh, Colleen Nofi and it's extracellular CRP syp. What is it? SEP, uh, exacerbates necrotizing enterocolitis, and she's from Cohen Children's Medical Center in New York. Hi, my name is Colleen Nofi, and I'm a general surgery resident at Northwell Health. Thank you for the opportunity to present my work entitled Extracellular CIRP exacerbates necrotizing Intercolitis. I'm the inventor of our related patent, and I have no other conflicts of interest to report. Necrotizing entercolitis or neck is a devastating gastrointestinal disease impacting premature infants whose pathophysiology is driven by a multitude of complex pathways that are not completely understood. Further, there remains limited treatment options and an unacceptably high morbidity and mortality risk. My work focuses on a protein called cold inducible RNA binding protein, or CIRP. Under biologic conditions, CRRP is found inside the cell where it acts as an RNA chaperone protein. However, in states of cellular stress, for example, in sepsis, CIRP escapes outside the cell. Once released from the cell, CRP becomes extracellular CIRP or ECIRP, where it then acts as a damp by enhancing the release of cytokines and chemokines, and amplifying the inflammatory cascade. Previously, we developed an ECIRP scavenging peptide named MFGE8 derived oligopeptide 3, or MOP 3, that removes ECRP from circulation to reduce inflammation. The aims of my work were to determine whether ECRP plays a role in exacerbating neck pathogenesis and to evaluate the therapeutic potential of our ECRP scavenging peptide, MOP 3, to protect against neck severity and mortality. To address our aims, we utilized a mirroring model of neck where pups were separated from mothers and subjected to a multitude of stressors, including hypercaloric formula gavage, enteric LPS, and hypoxic stress. We utilized wild type and CRP knockout pups to address AIM 1, and we utilized MP3 or vehicle treatment in wild type pups to address AIM 2. First, we found that CRP knockout protected pups from neck severity. Here you can see representative H&E stained intestinal sections. Upon quantification of neck severity, we identified a reduction in neck severity scores in CRP knockout pups, which is grossly seen by the preservation of the intestinal villi architecture and shown in the green bar here. Our next experiments further evaluated the impact of CRP knockdown in the intestines. We demonstrated a reduction in intestinal inflammation in CRP knockout mice subjected to neck, as assessed by mRNA levels of IL-6 and TNF alpha in the small bowel. Here you can see that reduction represented by the green bars. To evaluate the functional impact of intestinal injury and inflammation, we utilized fluorescently labeled Dextra administered enterically during our neck model, and measured systemic fluorescence as a measure of barrier dysfunction. For example, if the intestinal barrier was compromised, the fluorescent dextrand would leak out of the injured intestinal wall and be detectable in the serum. Here you can see the greatest fluorescence intensity in wild type neck pups, indicating a leaky intestinal barrier, where CRP knockout pups had reduced fluorescence intensity, indicating a preserved intestinal barrier. Finally, to probe the potential clinical impact, we evaluated survival differences between our animal strains. Remarkably, in the same model under the same conditions, there was 100% survival for CRP knockout pups subjected to neck, whereas the survival was only 65% for wild type pups. Transitioning to our therapeutic study, we first investigated the impact of our MOP 3 treatment on systemic markers in our neck model. Here you can see that MOP 3 functioned as designed, as there was a reduction in circulating ECRP levels in MOP 3 treated neck pups compared to vehicle. This reduction in ECRP also correlated with a reduction in other systemic inflammatory markers, including IL-6 and DNF alpha. In our neck model, treatment with MOP 3 also protected against neck severity. Here in the representative H&E stained intestinal sections, you can appreciate the preservation of the intestinal villi and associated reduction in neck severity scores indicated by the orange bar. Furthermore, treatment with MOP 3 reduced intestinal inflammation in neck as measured by mRNA levels of both IL-6 and TNF alpha. Again, in probing intestinal barrier function, we observed high fluorescence in our vehicle-treated neck pups, indicating intestinal breakdown, whereas MP 3 treated pups had significantly reduced fluorescence intensity, indicating protection of the intestinal barrier. Finally, when we compared overall survival of murine pups subjected to the neck model, we found a significant improvement in survival, up to 80% in pups treated with MP3, compared to only 50% for vehicle treated pups. This further supports a beneficial role of MOP 3 treatment in experimental neck. Altogether, our data in neck suggests that ECRP exacerbates neck pathogenesis by increasing inflammation and intestinal injury, whereas treatment with our novel peptide MOP 3 protects against neck pathogenesis by scavenging ECRP and preventing the deleterious downstream impacts. Thank you to my mentors, and I'm happy to take any any questions. Perfect. Erin relations, this is really exciting and thorough work, um, and a great presentation. My question for you is, what are your next steps? You've shown really impressive, um, therapeutic benefits of mop and mice, so how do we get this to kids? So, we, uh, of course, wanna further investigate uh optimal treatment of, uh, with our peptides. So if we can give it different routes, if it can be given internally. Um, we've also been looking at, um, other models trying to expand and make sure results are reproducible since we know not a single model of neck really recapitulates everything we exhibit in, um, neonates. So right now, we're, we're already showing, um, that MOB 3 is effective in other models. of ischemia reperfusion injury in the gut. So we're trying to really understand how we can maximize the beneficial impact because you can see we have the greatest impact with CRP knockdown, whereas our MOP 3 benefit is not quite the same level. So we're just trying to maximize what we can in our um pre-clinical models right now. Can I ask you a question about your, your models? When you create neck, what is the timing of the MOP 3 administration? Is it before the neck, um, Insult or is it as, as you say, it's treatment. So is it after you create the neck? So, we actually induce a 4-day neck models. So, the stressors are actually continuous for 4 days, and they, um, consist of a multitude of factors like LPS and formula gavage and hypoxia. And so, we give the MOP 3 treatment once per day, um, at the beginning of the model. So, the treatment is, is kind of, uh, ongoing with the insultive neck. Great work. Thank you very much. Thank you. Thank you. Great job.

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