This Funding Opportunity Announcement (FOA) encourages applications from institutions and organizations proposing original research aimed at the characterization of the function of neoepitopes and neoantigens in type 1 diabetes. This includes the function that post-translational modifications might have in the humoral and cell mediated autoimmune responses and overall in the etiology and pathophysiology of type 1 diabetes. Applications that include the discovery of neoantigens or neoepitopes are within the scope of this solicitation, but should propose a plan for integrating these discoveries with the present knowledge on established epitopes and antigens (e.g. autoantibodies for insulin, GAD65, IA-2, and ZnT8). In the long-term the goals of this initiative are to facilitate the development of better tools to monitor disease progression and treatment, and potentially to facilitate the development of personalized therapeutics.
Type 1 diabetes (T1D) is an autoimmune disease that is thought to be caused by genetic predisposition, environmental triggers, and a T-cell-mediated destruction of insulin-producing beta cells. Often, early stages of disease (pre-clinical) are indicated by the presence (in blood) of two or more autoantibodies with different specificities, including insulin, GAD65, IA-2, and ZnT8. Even though these major specificities have been known for many years and are used in the diagnosis of the disease, we still do not know what leads to the breakdown of the immune tolerance, and we have a poor understanding of the T1D etiology and pathophysiology. Furthermore, several new autoantigens (neoantigens) and neoepitopes have been discovered using innovative technologies, but their potential utility in monitoring disease development, progression and response to treatment has not been adequately explored and their role in the pathophysiology and etiology of T1D is unclear.
Post-translational modifications of proteins (e.g., citrullination, carbamylation, acetylation, deamidation) occur in autoimmune diseases such as rheumatoid arthritis (RA) and are correlated with pathology and poor prognosis. Inflammatory processes, including endoplasmic reticulum (ER) stress and environmental insults (e.g., smoking), contribute to the enhanced occurrence of post-translational modifications and risk in RA. The recent identification of post-translationally modified protein epitopes and the identification of T-cells that recognize these epitopes in samples from T1D patients suggests that similar processes may contribute to the T1D pathology. Importantly, the endocrine function of the beta cell and all its attendant processes are associated with a high susceptibility to ER stress. ER stress promotes apoptosis of beta cells, as well as post-translational modifications, which could precipitate or enhance autoimmune responses. Furthermore, the discovery in T1D patients of T-cells recognizing hybrid insulin peptides (polypeptides formed from the fusion of insulin fragments and other insulin secretory granule protein fragments) led to the compelling hypothesis that these neoepitopes contribute to the breakdown of immunological self-tolerance. Alternative open reading frame usage, and RNA splicing variants, have also been reported to be responsible for the generation of neoantigens that might be involved in the pathophysiology and etiology of T1D.
Overall it can be stated that, a better understanding of the contributions of autoantigens and neoantigens (e.g., those deriving from post-translational modifications) to autoimmunity and beta cell dysfunction in T1D is needed. Unbiased approaches to neoepitope identification are also likely to continue to identify new specificities that could add to our ability to identify the disease in its earliest stages. A better characterization of the epitopes involved in the autoimmune response in different people could differentiate endotypes of T1D, and lead to effective and safe, personalized therapies. For this purpose, it would be important that the proposed studies are put in the context of the presently known gene variations that increase the risk of developing T1D.
Overall, this initiative aims to expand our knowledge on the mechanism and potential function that autoantigens and neoantigens might have in the pathophysiology and etiology of T1D. In the long-term this knowledge should also facilitate the development of better tools to monitor disease progression and response to treatment, and lead to personalized therapeutics.
URL for more information:
Filed Under: Funding Opportunities