RESEARCH FOR A CURE
Propel A Cure is 501(c)(3) is all-volunteer nonprofit organization that raises funds for transformative research focused specifically on identifying the underlying causes of Crohn’s disease, the first step in the development of cures. Funding for this work comes primarily from patients, their families, and friends. Propel a Cure carefully allocates these donations, with over 98% of donations going directly to labs working on projects specifically selected by our leadership team with the help of our Scientific Advisory Board.
There is a long waitlist of promising research initiatives ready to launch with your support. Please help us accelerate progress toward cures on our donations page. All donations are tax-deductible for U.S. residents.
Ghosh Lab, University of California, San Diego
​​In April 2025, Propel a Cure awarded $100,000 to the Ghosh Lab at The University of California, San Diego, funding their 2-year breakthrough study, "Modulation of Dysfunctional Sensing and Signaling in Crohn's Disease." The team will be focusing on how the protein NOD2 interacts closely with another molecule called GIV, which acts like a brake to prevent overactive inflammation and support bacterial clearance in the human body. In Crohn's disease, certain genetic changes in NOD2 disrupt this teamwork, leaving the gut vulnerable to persistent inflammation, infection, and damage.
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Through this research, the Ghosh Lab aims to uncover how NOD2 and GIV work together to protect the gut, what happens when this partnership fails, and how to fix it.
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1. Learning How NOD2 and GIV Interact: They will investigate when and where these molecules connect inside immune cells and what strengthens or weakens their bond. This will help explain the precise role they play in sensing bacteria and controlling inflammation.
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2. Exploring the Consequences of Their Teamwork: By testing specific genetic changes and drugs in lab experiments, they will determine how NOD2 and GIV work together to clear harmful bacteria and regulate inflammation. They’ll also examine how disruptions to this partnership may lead to Crohn’s disease.
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3. Testing New Insights in Disease Models: Using advanced tools like "gut-on-a-chip" models and experiments in mice and human tissues, the team will see how their findings translate to real-world Crohn’s disease scenarios.
By discovering how to restore the partnership between NOD2 and GIV, the Ghosh Lab hopes to pave the way for new treatments that not only manage symptoms but address the root causes of Crohn’s disease. This work could lead to breakthroughs in understanding gut immunity, offering hope to millions affected by this challenging condition.
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UPDATE: April 2026
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There has been a major advance in this project since the last update.
Earlier work published in The Journal of Clinical Investigation showed that a partnership between NOD2 (the strongest Crohn's risk gene) and GIV (CCDC88A) is essential for macrophages to both clear microbes and control inflammation. When this partnership fails—as in Crohn's-associated NOD2 mutations—immune cells become activated but ineffective, allowing microbes to persist and inflammation to become chronic.
A new preprint (a manuscript that has been submitted to a journal and is awaiting peer review) reveals how this failure unfolds in real time.
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The key insight is that immune defense depends on a precisely timed "surge-to-plunge" program in cyclic AMP (cAMP), which is a type of rapid-fire messaging system in our bodies:
An early surge tempers inflammation
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A subsequent plunge is required for macrophages to kill microbes through phagolysosomal fusion, a cell's only way to eliminate threats or waste. Many pathogens encountered in Crohn's disease exploit this system by sustaining high cAMP, effectively disabling the cell's killing machinery.
This study shows that the NOD2–GIV partnership acts as a molecular toggle switch that enforces this timing. NOD2 first binds GIV to allow the early cAMP rise; GIV then switches to engage G proteins (a type of molecular switch), actively collapsing cAMP to enable microbial clearance. This tightly timed, structurally encoded switch functions as a decision-making circuit within immune cells. When the toggle fails, cAMP remains high, directly leading to downstream signals to remain hyperactive so that macrophages can ingest—but not destroy—bacteria. Infection persists, barrier integrity breaks down, and inflammation becomes self-sustaining.
Importantly, the mechanistic insights gained make a compelling case that two clear entry points emerge for treating Crohn's disease:
Upstream: Restore or stabilize the NOD2–GIV toggle (e.g., via molecular "glues" that reconstitute the interaction).
Downstream: Target the cAMP and its immediate signaling pathway to re-enable microbial clearance.
Conceptually, this reframes Crohn's disease from an overactive immune state to one of failed infection control and explains why antibiotics used in the treatment of Crohn's disease have not worked as well as they should have, because pathogens find safe havens within our immune cells that should have killed them otherwise.
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​UPDATE: January 2026
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In their recently published work in The Journal of Clinical Investigation, the Ghosh Lab showed that harmful bacteria can overwhelm key gut immune cells called macrophages when a critical molecular partnership breaks down. This partnership involves an immune sensor called NOD2 and a helper protein called GIV. When GIV levels are reduced—or when NOD2 carries mutations that prevent this molecular "handshake"—macrophages lose their ability to clear bacteria.
This discovery has been foundational. It has provided the first clear explanation for why people carrying certain NOD2 mutations face an extremely high risk of developing Crohn's disease.
Instead of eliminating harmful microbes, their macrophages allow bacteria to persist and multiply, driving chronic inflammation.
In follow-up work, the team uncovered how this molecular handshake protects immune cells from being hijacked. Bacteria attempt to take control of a universal cellular messaging system called cAMP—similar to an internal alarm network. When pathogens succeed, cAMP levels rise, disabling the macrophages' ability to kill microbes and calm inflammation. When the NOD2–GIV partnership is intact, immune cells regain control, cAMP levels are restrained, and threats are cleared.
The researchers mapped when and where this battle for control occurs, showing it is central to resolving infection. This work is currently under peer review prior to publication.
This latest advance goes even further. In a new perspective article, the researchers show that these molecular battles are not unique to IBD or to a single immune pathway. Instead, many microbes exploit the same short
molecular "codes" to confuse immune signaling, while the body has evolved matching systems to detect and neutralize these tricks.
This reframes immunity not just as detecting microbes, but as constantly verifying whether cellular messages are trustworthy. Importantly, this opens the door to new therapies aimed at restoring immune logic itself—rather than simply suppressing inflammation.
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UPDATE: September 2025
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Using advanced computer models powered by machine learning, Ghosh Lab researchers have discovered that, in many patients, harmful bacteria pile up in the gut. Normally, our body's immune "clean-up crew" cells, called macrophages, remove these threats. But in IBD, the very macrophages meant to both fight infection and calm inflammation seem to fail. More specifically, the team has uncovered with mathematical precision a hidden "battlefield" inside these cells. Bacteria have learned to hijack a universal cell signal called cAMP—a kind of rapid-fire text messaging system in our bodies. When cAMP runs wild, macrophages lose their ability to destroy germs, leaving patients trapped in cycles of infection and inflammation.
The team has also found our bodies carry a natural toggle switch that can reset the system. A sensor called NOD2 and a partner molecule called GIV work like a tag-team, handing off control to stop cAMP overload and restore balance. When this switch is "on," macrophages clear bacteria, protect the gut lining, and bring healing. Even more exciting, Ghosh Lab researchers have already shown, by recreating the battlefield using end-to-end human organoids and immune cells in culture dishes with microbes, that restoring this switch with specially designed molecules can rescue sick cells in the lab.​
Based on these new findings, these researchers have begun mapping a druggable pathway that could lead to new therapies for Crohn's patients.
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UPDATE: June 2025
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To better understand how NOD2 and GIV interact, over the past few months the team worked with mice and immune cells called macrophages. Mice that didn’t have GIV developed a type of gut disease that looked very similar to Crohn’s disease in humans, including swelling, tissue damage, and problems with the natural balance of gut bacteria. Most importantly, the team focused on a common version of NOD2 called "1007fs", which is found in many Crohn’s patients. This version is broken — it’s missing a key piece — and the researchers have now found out why that matters: It can’t connect to GIV. Without that connection, the immune system can’t do its job right, and bacteria aren’t cleared properly. This leads to more inflammation and damage in the gut.
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This is the first time scientists have clearly shown how this precise Crohn’s risk mutation, which was discovered originally in 2000, disrupts the immune system’s ability to clear bacteria.
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Now that the team understands this key piece of the puzzle, they are excited about the next step: exploring ways to fix or replace this broken connection between NOD2 and GIV as a new way to treat Crohn’s disease. Beyond mice, this team has the unique ability to test all their findings and hypotheses as well as potential drug-like small molecules and peptides in mini human guts called organoids. The team plans on doing those studies next.​​
Woolston Lab, Northeastern University
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In February 2025, Propel a Cure, in partnership with the Mendez Family Foundation, awarded a $100,000 grant to Northeastern University’s Woolston Lab for its cutting-edge proposal, "Defining the Role of Microbial Hydrogen Sulfide in Intestinal Inflammation."
Hydrogen sulfide is a molecule produced primarily by gut microbes and is associated with intestinal inflammation. Past studies have implicated it as a player in inflammatory bowel disease (IBD), but to date its precise role has been poorly understood. The Woolston Lab has engineered unique synthetic probiotic strains to use in this study that would be tested to gain insights into how and whether excessive production of hydrogen sulfide helps trigger IBD inflammation and what part it may play in disease progression.
Even more exciting, the research team has discovered that one of their newly developed strains has demonstrated particular promise in reducing the production of hydrogen sulfide in human-derived ex vivo studies, potentially leading to a new therapeutic that could treat or prevent IBD. Currently, there are no FDA-approved medicines targeting hydrogen sulfide for treating IBD. The development of a therapeutic to degrade toxic and pro-inflammatory intestinal hydrogen sulfide would be transformative for IBD patient care. Should preclinical animal testing prove successful, the Woolston Lab is already affiliated with a spinoff biotech startup – Concordance Therapeutics – which would be well positioned to bring such a therapeutic to clinical trials. This truly groundbreaking study will represent the first attempt to use engineered microbes to regulate sulfide levels in the gut microbiome.​
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UPDATE: April 2026
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Northeastern University's Woolston Lab continues to make progress toward better understanding the possible role of the molecule hydrogen sulfide – produced primarily by gut microbes – in the intestinal inflammation seen in IBD.
Previously, the team has experienced promising results in using specially engineered bacteria to deliver sulfide to mice. They have now begun testing strains that are engineered to sequester (remove) excess sulfide in the mice. The idea would be to bring sulfide levels back down to a healthy balance when they get too high, as higher levels have been associated with inflammation.
Experiments are still continuing and need to be repeated to establish robustness and statistical significance, but preliminary results have been encouraging. Mice that have been given the engineered bacteria have shown lower sulfide levels compared to mice that have received the control strain without the special modification.
Researchers have also been busy drafting the study's results from previous quarters for submission to an academic journal in the near future.
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UPDATE: January 2026
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This past quarter, the team has continued to demonstrate progress toward understanding the role of the molecule hydrogen sulfide (H2S) in Crohn's disease and therapeutic development.
They have now established that the lab's specially engineered microbes can deliver H2S in the intestine more effectively than existing chemical methods, suggesting that these microbes are an ideal tool for testing the elevation of intestinal H2S in laboratory mice. This is a critical step toward understanding the possible role of H2S in Crohn's.
The scientists have also begun testing the engineered microbes in dextran sulfate sodium (DSS)-induced Crohn's mouse models (as opposed to normal mice versions). These specialized mice mimic the effects of IBD seen in human patients.
Using their H2S-producing and -consuming microbes, the team is further investigating how the elevation or reduction of H2S impacts Crohn's disease pathology. They are thus far encouraged by study results and, in the future, will be experimenting with the delivery of different levels of H2S, as well as expanding the number of mice in the study.
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UPDATE: September 2025
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Over the last few months, the lab has made progress in understanding the fundamental role of H2S in Crohn's disease. They have now generated proof-of-concept data that their engineered bacteria can degrade H2S in the mouse gut. This is a critical step toward developing a probiotic to degrade intestinal H2S, which they believe plays a key role in exacerbating Crohn's inflammation.
UPDATE: June 2025
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The team engineered bacteria in the lab designed to try to produce excess hydrogen sulfide in the animal gut. They have now tested their engineered bacteria in animals, observing a greater than 5-fold increase in intestinal hydrogen sulfide. This is a critical milestone because elevating hydrogen sulfide levels is experimentally difficult due to its gaseous nature. The team now has a tool capable of elevating intestinal hydrogen sulfide levels – mimicking what is seen in Crohn’s patients – that will help us understand its fundamental role.
In the next phase of this work, the Woolston Lab will be able to use their engineered bacteria to study how high levels of hydrogen sulfide impact Crohn’s pathology, which is a significant step forward.
Promakhos Therapeutics, Boston
​In February 2024, Propel a Cure awarded a 2-year $100,000 Trailblazer Grant to Promakhos Therapeutics for its innovative proposal, "Validating the Role of Mucosal Innate Immune Deficiency in Crohn’s Disease." Promakhos is a Boston-area startup housed in the Pagliuca Harvard Life Lab, an incubator lab co-managed by Harvard University and Lab Central.
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Thanks to this support from Propel a Cure and other funding sources over the last couple of years, Promakhos has been able to advance the development of an oral non-immunosuppressive precision therapy that their team believes has the potential to slow, halt, or even reverse Crohn’s disease progression. This oral therapy, based on research suggesting that the mucosal innate immune response is not activated correctly in Crohn’s patients, aims to restore a natural biological signal that appears to be missing to address both barrier dysfunction and immune cell overactivation.
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In preclinical studies, it has shown promising results, promoting intestinal healing, clearance of invasive microbes and gut microbiome diversity, as well as reducing bowel inflammation. Importantly, this candidate drug has a selective and distinct mechanism of action that occurs upstream of current medications. Promakhos’ approach is also supported by a biomarker strategy designed to identify patients who may be most likely to respond to treatment.
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In Spring 2026, Promakhos co-founder and CEO Katerina Chatzi received the prestigious Harvard President's Innovation Challenge Award for alumni & affiliates of Harvard, recognizing groundbreaking solutions addressing global challenges. Promakhos researchers next hope to move their candidate drug to human safety studies in their drive to bring transformative solutions to Crohn’s patients.
Vincent van Unen Research Group, Leiden University Medical Center, the Netherlands
For its first grant, Propel a Cure, in partnership with the nonprofit Cure for IBD, awarded $58,000 to support a groundbreaking study from the Vincent van Unen Research Group at Leiden University Medical Center in collaboration with Stanford University, entitled "Shared CD4+ T Cell Receptor Specificity Groups in Crohn’s Disease and Ulcerative Colitis." This research helped scientists better understand what the immune system may actually be recognizing and responding to in inflammatory bowel disease (IBD) patients.
Although Crohn’s disease (CD) and ulcerative colitis (UC) can look very different clinically, the research team found that patients with both conditions shared similar T-cell receptor (TCR) patterns. TCRs are structures on immune cells that help them recognize specific targets in the body. These shared patterns suggest that CD and UC may involve some of the same immune triggers. The researchers also found that these patterns were linked to HLA-DRB1, a gene region known to influence IBD risk.
The scientists analyzed more than 3 million T-cell sequences from CD and UC patients, along with healthy controls, and identified five immune patterns strongly associated with IBD. These patterns were found in patients in both disease groups, suggesting that the two conditions may share common immune pathways.
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Click here to see the pre-press abstract of the study resulting from this research.