Autoimmune thyroid diseases (AITD) frequently develop together with type 1 diabetes (T1D), a combination considered a variant of the Autoimmune Polyglandular Syndrome type 3 (APS3v). Our goals are to identify the joint susceptibility genes for AITD+T1D (APS3v), to dissect the mechanisms by which they cause disease, and to translate this knowledge into new therapies. In the last grant cycle we made substantial progress toward these goals: (1) We mapped new susceptibility genes/loci for APS3v using whole genome approaches; (2) We discovered a unique HLA-DR-pocket signature critical for the development of APS3v; (3) We identified 4 pathogenic thyroid & islet peptides that bind to the APS3v-specific HLA-DR & activate T-cells; (4) We identified genetic-epigenetic interactions that trigger AITD & T1D; (5) We discovered a compound, Cepharanthine, that blocks thyroglobulin peptide presentation & prevents autoimmune thyroiditis in mice. Building on these findings we propose to: (1) Sequence 3 APS3v loci we mapped to identify rare variants predisposing to APS3v; and (2) Translate our discovery of the APS3v-DR pocket into new therapies by blocking this pocket. Our hypothesis is that in addition to common variants, rare non-HLA variants are also critical to the joint etiology of AITD+T1D, and that identifying them will reveal new mechanisms & therapeutic targets; furthermore, we hypothesize that binding of pathogenic peptides to the APS3v-DR pocket & their presentation to T-cells triggers APS3v, and that blocking pathogenic peptide binding to HLA-DR can be used to treat or prevent APS3v.
Our specific aims are:
Specific Aim 1 : Identifying rare variants in 3 loci (2q, 8p, Xp) that are linked with APS3v using targeted next generation sequencing (NGS) in our unique dataset of families in which AITD+T1D cluster. Identified variants that are predicted to alter gene function will be replicated in 2 large cohorts of APS3v patients and families.
Specific Aim 2 : Screening of a large library for small molecule inhibitors (SMI's) that block pathogenic peptide binding to the APS3v-DR pocket to identify hits. Hit SMI's will be confirmed in vitro, ex vivo and in vivo. Lead SMI's will be optimized by medicinal chemistry to improve potency, selectivity, & pharmacokinetic properties.
Specific Aim 3 : Designing D-amino acid peptide blockers of pathogenic peptide binding to the APS3v HLA-DR pocket. We will design in silico D-amino acid peptides (D-peptides) predicted to block binding and presentation of pathogenic thyroid/islet peptides. Predicted D-peptide blockers will be confirmed in vitro, ex vivo, and in vivo. In summary, our multidisciplinary translational project builds on the knowledge gained in the last grant period. Our goals are to continue our successful gene discovery using targeted NGS of mapped APS3v loci to identify new therapeutic targets, and to pursue pre-clinical development of novel therapies for APS3v by blocking the APS3v-DR pocket we identified. The strength of our therapeutic approach is that it is both selective as only T- cells recognizing pathogenic peptides are targeted and personalized since only patients carrying the APS3v- DR will be treated. Our studies will hopefully lead to new therapies for APS3v, as well as for AITD and T1D.

Public Health Relevance

Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, and type 1 diabetes (T1D) frequently occur together in the same individual. The co-occurrence of AITD and T1D is strongly influence by joint susceptibility genes. The overall goal of our studies is to identify and characterize the shared susceptibility genes for AITD and T1D and to use this knowledge to develop new therapies for these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
6R01DK067555-12
Application #
9857903
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Akolkar, Beena
Project Start
2005-03-01
Project End
2022-03-31
Budget Start
2019-01-01
Budget End
2019-03-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461
Faustino, Larissa C; Lombardi, Angela; Madrigal-Matute, Julio et al. (2018) Interferon-? Triggers Autoimmune Thyroid Diseases via Lysosomal-Dependent Degradation of Thyroglobulin. J Clin Endocrinol Metab 103:3678-3687
Lombardi, Angela; Tsomos, Effie; Hammerstad, Sara S et al. (2018) Interferon alpha: The key trigger of type 1 diabetes. J Autoimmun 94:7-15
Li, Cheuk Wun; Osman, Roman; Menconi, Francesca et al. (2017) Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes. J Autoimmun 76:1-9
Blackard, Jason T; Kong, Ling; Lombardi, Angela et al. (2017) A preliminary analysis of hepatitis C virus in pancreatic islet cells. Virol J 14:237
Lombardi, Angela; Tomer, Yaron (2017) Interferon alpha impairs insulin production in human beta cells via endoplasmic reticulum stress. J Autoimmun 80:48-55
Hammerstad, Sara Salehi; Stefan, Mihaela; Blackard, Jason et al. (2017) Hepatitis C Virus E2 Protein Induces Upregulation of IL-8 Pathways and Production of Heat Shock Proteins in Human Thyroid Cells. J Clin Endocrinol Metab 102:689-697
Tomer, Yaron; Dolan, Lawrence M; Kahaly, George et al. (2015) Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. J Autoimmun 60:32-9
Lombardi, Angela; Inabnet 3rd, William Barlow; Owen, Randall et al. (2015) Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis. J Clin Endocrinol Metab 100:E1-10
Li, Cheuk Wun; Concepcion, Erlinda; Tomer, Yaron (2015) Dissecting the role of the FOXP3 gene in the joint genetic susceptibility to autoimmune thyroiditis and diabetes: a genetic and functional analysis. Gene 556:142-8
Hammerstad, Sara Salehi; Grock, Shira Frankel; Lee, Hanna J et al. (2015) Diabetes and Hepatitis C: A Two-Way Association. Front Endocrinol (Lausanne) 6:134

Showing the most recent 10 out of 50 publications