Hessner, Martin John, PhD
Serum/plasma induced signatures as T1D biomarkers
General Research Subject: Type 1 Diabetes
Focus: Gene Chips and Microarrays, Genetics, Genetics\Type 1 Diabetes, Immunology
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Successful prevention of type 1 diabetes (T1D) requires early identification of humans deemed to develop the disease. Biomarkers that can be used to monitor the initiation of pancreatic beta cell autoimmune responses and the progression of T1D are essential to achieve the goal of accurate and early prediction of its development. Dr. Hessner has developed a highly sensitive and comprehensive assay to detect subtle changes of soluble factors present in the blood as a biomarker. The changes of the soluble factors in the blood most likely reflect the ongoing inflammatory process associated with the initiation and progression of T1D. This method has been demonstrated to have a predictive value for human T1D even before the appearance of islet autoantibodies, a method currently used for prediction, and at more than 5 years prior to disease onset. The same approach has also been used to detect changes indicative of progressive autoimmune diabetes in both cross-sectional and longitudinal studies in the BioBreeding (BB) rat model of T1D. Non-obese diabetic (NOD) mice develop spontaneous T1D and have been used extensively to study the pathogenic basis of the disease. To build upon these exciting findings, the overall goal of this application is to integrate NOD mouse model to the existing human and BB rat studies to mechanistically understand the serum-induced T1D transcriptional signature and to further improve its clinical value.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Biomarkers are needed in Type 1 diabetes (T1D) that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, auto-antibody development; 2) define inflammatory mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. However, the inflammatory state associated with Type 1 Diabetes (T1D) is difficult to measure directly in peripheral blood samples. To fill this gap, we have developed and applied a novel "blood test" that relies on the exquisite sensitivity of healthy cells to respond to changes in their environment. The assay is performed by growing white blood cells derived from a healthy individual with test subject serum or plasma (the liquid portion of blood). Inflammatory factors present in the serum activate genes in the "reporter" cells; this is measured with a microarray, a technology that allows us to measure activity levels (gene expression) for thousands of genes at once.
We find that serum from human T1D patients induces a characteristic gene expression signature, distinct from that induced by sera of healthy controls, long-standing T1D patients, or patients possessing other inflammatory diseases. Importantly, the signature is detected as much as 5 years prior to T1D onset and includes many genes under control of the inflammatory mediator interleukin 1 (IL-1). Our data suggest that this indirect, yet sensitive approach may be useful in predicting T1D in "at risk" subjects and monitoring changes in the inflammatory state during disease progression (Aim 1) as well as during therapeutic intervention (Aim 2).
Completion of this study has the potential to 1) reveal predictive markers reflective that may allow for pre-onset disease prediction; 2) identify relevant inflammatory pathways that may serve as targets for either pre or post onset therapeutic intervention aimed at preserving insulin producing beta cells; 3) allow measurement of changes in the inflammatory state associated with therapeutic intervention.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
There are many different inflammatory mechanisms in humans. Our methodology not only tells us if inflammation is present, but informs us as to which inflammatory pathways are activated. Such information can be useful in monitoring the effect of a therapeutic intervention by revealing the degree to which an inflammatory response or components of an inflammatory response have been attenuated. We will test this possibility in Aim 2 of the project, where we will examine subjects enrolled into two different clinical trials.
We see potential future applications of this approach in clinical interventions. These include interventions prior to onset and post-onset, as well as therapies that may be administered in the islet transplant setting.
We also realize that the activated inflammatory pathways that lead to T1D may differ between patients. Our approach may help to identify these differences and facilitate development of individualized therapies.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Autoimmune diseases afflict a significant portion of our society. T1D represents an important area where I can, as a molecular biologist/immunologist, apply my expertise in functional genomics. This award will enable further development of our novel approach that aims to fill the need for new biomarkers in T1D (both for disease prediction as well as defining the activated immunological pathways and the degree to which therapeutic interventions can normalize them). Our success in T1D will be directly applicable to other inflammatory diseases.
In what direction do you see the future of diabetes research going?
I see the continued investigation of targeted immuno-modulatory therapies combined with strategies regenerating/replacing beta cell mass.
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