Flavell, Richard A.
Immunity and Diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Genetic modification of the mouse genome by transgenesis or gene knockout techniques are used to either over-express, alter or delete gene function. Using this technology, the functions of genes can be investigated in situ. Using this technology, many genes of the immune system can be analyzed and their roles in the inflammatory, innate, and adaptive immune response have been analyzed. Projects outlined in this proposal will use this technology to either investigate how inflammation is involved in initiation of Type II diabetes or generate a mouse model of human immune responses leading to Type I diabetes.
Mentor: Flavell, Richard, PhD Postdoctoral Fellow: Yu, Hua
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
It has long been known that type 1 diabetes is an inflammatory disease, characterized by autoreactive T-cell infiltration into the pancreatic islets. Although type 2 diabetes is traditionally received as a metabolic disorder, recent data point out that inflammasome and proinflammatory cytokines, such as IL-1? can cause insulin resistance and glucose toxicity. Therefore, our research will focus on the role of inflammation in both types of diabetes.
The first project is to investigate the metabolic phenotypes of mice genetically deficient in inflammasome components including ASC, Caspase-1, NLRP3 and other NLRs. Our preliminary data showed that Asc-/- mice were more prone to develop obesity and insulin resistance when giving a high fat diet. However, the current published data all indicated Caspase-1 and Nlrp3 deficiency improved insulin sensitivity. The discrepancy of metabolic phenotypes between Nlrp3-/- and Asc-/- suggest that some NLR other than NLRP3 may act upstream of ASC to regulate the metabolism and the action of inflammason/Caspase-1 pathway in metabolic syndromes is truly complex and poorly understood. This study will help to provide an improving picture of how inflammasomes modulate the pathogenesis of metabolic dysfunction and may unravel potential drug targets for type 2 diabetes therapies.
The second project is to develop a humanized mouse model of Type 1 diabetes. By utilizing transgenesis and gene knock out techniques, we have generated a mouse model, in which a number of mouse cytokines or receptor genes have been replaced with their human counterparts. We plan to visualize and assess the function of islet reactive human T cells in vivo, for example, do they proliferate, secrete proinflammatory cytokines or attack the islets? The outcome of this project will help us to understand the disease mechanisms in a mimicking human system and provides a safe, cheap and reliable animal model to evaluate potential vaccines or other promising candidates for diabetes treatment.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The results obtained from these two projects will have important clinical implications. The first project will help us to elucidate the different role of NLRs in regulating glucose metabolism. Since our preliminary data suggests that the drug targeting Nlrp3 or Asc may have completely opposite effects, the outcome of this project may help to specify the drug target and also improve the drug safety. The second project will help to bridge the translational gap between rodent models and humans. “Humanized” animal model could permit the in vivo investigation of human immune system, analysis of the pathogenesis of human diabetes at various stages and allow pre-clinical testing without putting individuals at risk.
Why is it important for you, personally, to become involved in diabetes research?
Diabetes is the seventh leading cause of death in the United States and 8.3% of the total population has this disease. While the prevalence of diagnosed diabetes keeps rising, its cause is still not fully understood. I continue to be involved in diabetes research because it can help us to better understand the underlying mechanism and provide the information required for the cure. I hope the ADA mentor-based award will inspire more young scientists/clinicians to undertake basic research related to diabetes and finally become the independent researcher after the training.
In what direction do you see the future of diabetes research going?
As inflammation is associated with both type 1 and type 2 diabetes, the
development of anti-inflammatory approaches may stand as promising
immunotherapeutic strategy. Specifically, in type 1 diabetes, further
research would focus on inducing immune tolerance and applying the
therapeutic agents (e.g. Tregs) to inhibit ongoing pathogenic T-cell
responses and reverse established pathology. In type 2 diabetes,
modulating specific proinflammatory cytokine pathways in adipose tissue,
skeletal muscle and liver to improve the glucose tolerance or in the
islets to increase beta cell mass is worthy to pursue. In addition,
efforts to develop murine models that faithfully recapitulate human
diabetes need to be further investigated.
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