Objective
The goal of this project is to understand why insulin-producing beta cells carrying a specific genetic mutation are destroyed so rapidly during autoimmune attack. Using advanced genomic tools, we aim to map the precise molecular changes that make these cells fragile and prone to self-destruction when exposed to inflammation. By identifying these vulnerability pathways, we hope to lay the groundwork for therapies that strengthen and protect beta cells directly — rather than relying solely on suppressing the immune system — ultimately helping to preserve insulin production in people with type 1 diabetes.
Background Rationale
Type 1 diabetes occurs when the immune system mistakenly attacks and destroys the beta cells of the pancreas — the only cells in the body that produce insulin. Without insulin, blood sugar cannot be regulated, requiring lifelong daily injections. Current treatments focus on replacing insulin or dampening the immune system, but a deeper understanding of why beta cells are lost so rapidly could lead to better therapeutic strategies.
Our research uses a mouse model carrying a rare human mutation called STAT1 Gain-of-Function, which causes severe autoimmune disease including early-onset type 1 diabetes. We originally expected this mutation to work by disabling the immune system's built-in safeguards. However, our preliminary data suggest these safeguards may still be partially functional, pointing to an additional factor: the beta cells themselves may be inherently more fragile.
This is consistent with what we know about beta-cell biology. Compared to other cell types, beta cells operate under uniquely stressful conditions — they have limited defenses against oxidative damage, they are under constant strain from the demands of producing insulin, and their survival depends on a small set of critical genes. We believe the STAT1 mutation exploits each of these vulnerabilities, quietly priming beta cells to overreact and self-destruct when they encounter the inflammation that accompanies autoimmune attack. Understanding this built-in fragility could open the door to a complementary treatment strategy: in addition to restraining the immune system, we could develop ways to make beta cells more resilient, helping them survive and continue producing insulin even under immune stress.
Description of Project
Type 1 diabetes is an autoimmune disease in which the immune system mistakenly destroys the insulin-producing beta cells of the pancreas. Without these cells, the body cannot make insulin, leading to lifelong dependence on insulin injections. Understanding how and why beta cells are destroyed remains a central question in the field.
Our lab studies a rare genetic mutation called STAT1 Gain-of-Function, which causes severe autoimmunity in humans, including early-onset type 1 diabetes. To understand how this mutation drives disease, we developed a novel mouse model. We initially expected to find that the immune system's regulatory cells — which normally keep immune responses in check — were fully disabled by the mutation. Our early data suggest this may not entirely be the case, raising the possibility that factors beyond immune dysregulation contribute to the rapid destruction of beta cells.
This led us to look at the other side of the equation: the beta cells themselves. We now propose a "Two-Hit" model of beta-cell fragility. The first hit is the mutation, which quietly rewires the internal machinery of beta cells, making them vulnerable without causing obvious problems — mice carrying the mutation have normal blood sugar early in life. The second hit comes when inflammation arrives, as it inevitably does in autoimmune diabetes. Rather than mounting a measured stress response, these beta cells appear to overreact catastrophically, participating in their own destruction through runaway stress signaling and cell death.
To test this model, we are using two advanced genomic technologies — Single Cell Multiome and CUT&RUN — to build a molecular map of this vulnerability. If we can identify the specific pathways that make beta cells fragile, we can begin developing therapies that protect them directly, allowing them to survive and produce insulin even under immune attack. This reframes type 1 diabetes not just as a disease of immune attack, but of target-tissue vulnerability.
Anticipated Outcome
We expect to produce a detailed molecular map of beta-cell fragility — identifying the specific genes, regulatory switches, and signaling pathways that make beta cells carrying the STAT1 mutation vulnerable to destruction under inflammatory stress. These findings will reveal how the mutation primes beta cells to overreact to immune signals and pinpoint the critical points at which this process could be interrupted.
Relevance to T1D
Type 1 diabetes results from the immune-mediated destruction of insulin-producing beta cells, and most therapeutic efforts have focused on modulating the immune response. Our work adds a complementary perspective by investigating the beta cell's own contribution to disease progression. If beta cells carrying certain genetic changes are inherently more prone to failure under immune stress, then protecting these cells — making them more resilient — could slow or prevent the loss of insulin production. This is directly relevant not only to patients with STAT1 Gain-of-Function mutations, but potentially to the broader type 1 diabetes population, where beta-cell stress responses and inflammatory signaling through the same STAT1 pathway are increasingly recognized as contributors to disease. Therapies that "harden" beta cells against destruction could work alongside immune-based approaches, offering a more complete strategy for preserving beta-cell function and reducing dependence on exogenous insulin.