Objective
1. Understanding the molecular mechanism of gene (X) mediated beta cell neogenesis
2. Screening for potential inducer of beta cell neogenesis based gene (X) activity
3. Developing a new gene therapy for type 1 diabetes target gene (X)
Background Rationale
Type 1 diabetes mellitus (T1D) is a disease characterized by an absolute deficiency of insulin-producing beta cells in the pancreas. Strategies to protect the beta cells from immune attack may ultimately help prevent type 1 diabetes before its onset. However, we are still not able to identify individuals at risk of type 1 diabetes in the general population. Autoimmune destruction of beta cells often starts very early in life. Therefore, a successful immune intervention may help prevent disease in some individuals but cannot help patients with long-standing disease or in whom the onset of disease could not be predicted in time for prevention. For these patients, strategies to restore beta cell mass and insulin production is urgently needed and will still be essential even when successful immune therapies exist.
In clinical, replacement therapy with cadaveric islets has been shown as a proof to reverse diabetes in 87.5% of patients at 1 year after transplantation. However, the availability of islets supply is limited for broader application to more T1D patients. Recent breakthroughs in deriving glucose responsive beta-like cells from human pluripotent stem cells have given a boost for beta cell replacement therapy. However, the needs of long-term immune suppression when transplanting allogenic human stem cell derived beta cells still overshadow this approach. Unlike in rodents, adult beta cell replication is extremely rare in humans. In long-standing type 1 diabetes patients, very few beta cells are left in the pancreas, and it would be slow to fully restore their beta cell mass only by promoting beta cell replication.
A different strategy is to replenish the beta cell mass by trans-differentiation of new beta cells from other cell types, such as pancreatic alpha cells, acinar cells and duct cells. It has been long hypothesized that pancreatic duct epithelium serves as a pool of progenitors for both the islet and acinar tissues after birth and into adulthood. Based on the further evidence, at least some, if not most, of the pancreatic duct cells in rodents and in humans can serve postnatally as beta cell progenitors although this process may not be robust. However, questions remain as to exactly how beta cell neogenesis is controlled?
Description of Project
Here, we employed an unbiased whole-genome CRISPR screen, and discovered that the deletion of a gene (X) that promotes human beta cell neogenesis from human pancreatic duct cells (Induce human primary ductal cell transdifferentiated to beta-like cells efficiently). However, the mechanism of gene (X)-mediated beta cell neogenesis is completely unknown. The proposed research herein aims to enhance our understanding of this gene-mediated beta cell neogenesis and explore the possibility of developing novel treatment or therapy for type 1 diabetes based on the knowledge we will gain from the study.
Anticipated Outcome
1. A better understanding of the role gene (X) plays in pancreatic beta cell neogenesis.
2. Find inhibitors that target gene (X) as a potential inducer for beta cell neogenesis.
3. Understand whether mutation of gene (X) can really promote beta cell neogenesis in vivo in the pancreas.
4. Figure out whether gene (X) loss-of-function induced beta cell neogenesis is able to reverse diabetes in mouse models.
Relevance to T1D
Despite active research, no therapy to date has been able to induce beta cell regeneration in humans. Our study will better understand the mechanism that how human pancreatic duct cells were trans-deafferented to beta or beta-like cells by a single gene (X) mutation. And also explore the possibility of developing novel treatments or therapy for type 1 diabetes based on the knowledge we will gain from the study.