Browsing by Author "Mathews, Clayton E."

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    A genomic data archive from the Network for Pancreatic Organ donors with Diabetes
    (Springer Nature, 2023-05-26) Perry, Daniel J.; Shapiro, Melanie R.; Chamberlain, Sonya W.; Kusmartseva, Irina; Chamala, Srikar; Balzano-Nogueira, Leandro; Yang, Mingder; Brant, Jason O.; Brusko, Maigan; Williams, MacKenzie D.; McGrail, Kieran M.; McNichols, James; Peters, Leeana D.; Posgai, Amanda L.; Kaddis, John S.; Mathews, Clayton E.; Wasserfall, Clive H.; Webb-Robertson, Bobbie-Jo M.; Campbell-Thompson, Martha; Schatz, Desmond; Evans-Molina, Carmella; Pugliese, Alberto; Concannon, Patrick; Anderson, Mark S.; German, Michael S.; Chamberlain, Chester E.; Atkinson, Mark A.; Brusko, Todd M.; Pediatrics, School of Medicine
    The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.
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    Efficient transduction of pancreas tissue slices with genetically encoded calcium integrators
    (bioRxiv, 2025-03-25) Lazimi, Charles S.; Stis, Austin E.; Panzer, Julia K.; Hiller, Helmut; Beery, Maria L.; Linnemann, Amelia K.; Stabler, Cherie L.; Mathews, Clayton E.; Phelps, Edward A.; Pediatrics, School of Medicine
    This study combines live pancreas tissue slices with adenoviral transduction of the Calcium Modulated Photoactivatable Ratiometric Integrator 2 (CaMPARI2) biosensor for high-throughput analysis of islet calcium responses. Pancreas slices preserve islets within their native microenvironment, adding tissue context to the study of islet function and pathology. A key challenge of the pancreas slice model has been efficient transgene delivery while maintaining viability and function. Here, we demonstrate a robust adenoviral gene delivery approach using targeted and universal promoters. By transducing slices with CaMPARI2 and applying 405 nm photoconverting light, we permanently marked glucose-induced calcium activity across entire islet populations while preserving the in situ tissue context. Applied to nPOD donor tissues, including from individuals with type 1 diabetes, type 2 diabetes, and non-diabetic controls, this approach demonstrated glucose responsive CaMPARI2 labeling that correlated with insulin secretion. Integrating CaMPARI2 with pancreas slices enables multiplexed analyses, linking a functional readout with spatial context through immunostaining or gene expression to advance understanding of human islet behavior.
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    Lipid mediators and biomarkers associated with type 1 diabetes development
    (American Society for Clinical Investigation, 2020-08-20) Nelson, Alexander J.; Stephenson, Daniel J.; Bone, Robert N.; Cardona, Christopher L.; Park, Margaret A.; Tusing, Ying G.; Lei, Xiaoyong; Kokotos, George; Graves, Christina L.; Mathews, Clayton E.; Kramer, Joanna; Hessner, Martin J.; Chalfant, Charles E.; Ramanadham, Sasanka; Pediatrics, School of Medicine
    Type 1 diabetes (T1D) is a consequence of autoimmune β cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2β (iPLA2β) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2β can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering β cell death. As MΦ are early triggers of immune responses in islets, we examined the impact of iPLA2β-derived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of MΦ production and plasma abundances of eicosanoids and sphingolipids. We find that (a) MΦNOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2β reduces production of select proinflammatory lipids, promotes antiinflammatory MΦ phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D.