Objective
Majority of our DNA is made up of genes that do not produce any proteins. This ‘non-protein-coding’ compartment was previously thought to be junk and not contributing to any cellular functions. However, in recent years, non-coding RNAs (produced from non-coding DNA) are demonstrated to be important in several processes (including insulin production) and in disease onset/progression. These non-coding RNAs are also released in circulation, enabling them to be biomarkers of disease progression when measured in circulation (blood). This study aims to use our non-coding RNA (microRNA) biomarker signature, we identified through immunology, insulin-producing islet cell death, development and Type 1 diabetes (T1D) progression studies; on different longitudinal cohort of blood samples collected from mother-infant dyads for the first few years in life at different time points, which have groups that progressed and not progressed to T1D later in life. This study will identify the use of microRNA biomarkers for predicting T1D progression in the span from pregnancy, birth to early childhood leading the way to potentially providing new targets for intervention and prevention. This research is timely as there are current therapies to prevent beta-cell loss. Initiating immune-modulatory therapies earlier in high-risk populations when little to no insulin producing-cell damage has occurred may further delay or even prevent the requirement for exogenous insulin (thus preventing or delaying the onset development of T1D). This would be particularly life-changing for children where the diagnosis of T1D before 10 years of age is associated with a 16-year reduction in life expectancy.
Background Rationale
Currently genetic (genetic risk scoring) and biochemical (antibody) tests are used to screen for Type 1 diabetes (T1D) progression. Although, there are strong genetic links, 90% of individuals who develop T1D do not have any family history of T1D. Also, autoantibodies tests clinical presentation of T1D progression can take from months to years; and antibodies themselves are consequences of the underlying pre-existent pathology (a reminder of the “streetlight effect”). Current genetic and biochemical tests do not entirely explain the progression of T1D. MicroRNA are small RNA molecules that do not code for protein, known to be important biomarkers and regulators of cellular processes. They are also released in circulation, therefore can be measured in blood. MicroRNAs are established prognostic biomarkers of cancer progression, although not yet in T1D progression. Our human islet, immunity and T1D studies have led us to identify a signature of microRNAs that could potentially predict T1D progression early. This proposed research will measure this microRNA signature in a small amount blood samples from different existing longitudinal cohort studies to predict islet autoimmunity and T1D progression within blood samples of pregnancy (maternal), cord (at birth) and (minimally invasive) heel-prick samples of neonates and children in the first two years of life.
Description of Project
Currently genetic (genetic risk scoring) and biochemical (antibody) tests are used to screen for Type 1 diabetes (T1D) progression. However, many individuals with T1D have no family history of T1D, and in addition autoantibodies are the consequences of underlying pathological mechanisms leading to T1D, and are therefore, not the best biomarkers for T1D progression. Since current tests do not truly capture T1D progression, they are a reminder of the “streetlight effect”.
Regulatory molecules (such as microRNAs) have not only been identified are fine regulators of insulin production but can be robust biomarkers. MicroRNA biomarkers are well-established in cancer prediction and treatment efficacy, although as of not yet established in T1D. Through our previous research on autoimmune-model of diabetes, pancreas development, insulin production and clinical T1D progression; we identified a signature of microRNA biomarkers that has the potential to predict T1D risk. Here, we will profile and assess the potential of this biomarker signature in samples already collected from mother-infant dyads from existing longitudinal cohort study to predict islet autoimmunity and T1D progression within the first two years of life.
Anticipated Outcome
It is anticipated that this microRNA signature will help identifying the risk for T1D progression in early life. Different cohorts from within Australia and internationally (from Denmark and Qatar) will provide an additional assessment of ethnic and population differences, which is anticipated to observe differences in the microRNA signature, yet will still be predictive of T1D risk for progression. Early detection will help prevent diabetes with new and emerging therapies.
Relevance to T1D
Identification of T1D progression early with this microRNA signature will help determine the initiation of early immune-modulatory therapies in high-risk populations when little to no beta-cell damage has occurred that can further delay or even prevent the requirement for future exogenous insulin. This would be particularly life-changing for children where the diagnosis of T1D before 10 years of age is associated with a 16-year reduction in life expectancy.