It is likely that a cure for diabetes will involve multiple approaches, rather than one strategy being suitable for all patients. Diabetes is characterized by loss of beta-cells, but little is known about how to prevent that loss. Two logical approaches are to prevent beta-cell death, or to restore beta-cells after they are lost. This proposal will carry out fundamental studies that will inform both approaches. The long-term goal is to identify potential therapeutic targets for ameliorating beta-cell loss in diabetic patients. The approach is to use transgenic zebrafish as a model of neonatal diabetes and endoplasmic reticulum (ER) stress. The models include two different transgenic lines that express a human proinsulin containing a single gene mutation. Both mutations cause neonatal diabetes in humans. Such mutations prevent correct folding of the molecule and prevent it from being secreted. The misfolded proinsulin is retained in the ER, where it accumulates and eventually causes cell death. However, adult zebrafish, unlike mammals, have the ability to regenerate beta-cells. This provides a unique opportunity to identify genes that are required for maintaining beta-cell mass.
Specific Aim 1 will study factors that positively and negatively influence beta-cell death. The focus is on characterizing the ER-stress response in beta-cells that accumulate misfolded proinsulin in the ER. The strategy is to quantify relative gene expression levels of conserved factors in the known vertebrate ER homeostasis pathways.
Specific Aim 2 will compare differential gene expression in wild-type islets versus mutant, regenerative islets. Whole transcriptome analysis will identify genes that are required for maintenance and regeneration of beta-cell mass. This unbiased approach will also identify genes that are critical for maintaining ER homeostasis. The proposed research is innovative because it utilizes novel transgenic lines of zebrafish that will allow the in vivo study of beta-cell biology and regeneration, and because it uses disease-specific ablation. The proposed research is significant because it is expected to be a step forward in identifying therapeutic targets for maintaining or restoring beta-cell mass in human diabetic patients.

Public Health Relevance

Diabetes is a leading cause of morbidity and mortality in the U.S, and there is no cure. This project will reveal fundamental insights into how pancreatic cell mass is maintained and regenerated. The knowledge gained will be critical for developing therapies to prevent cell loss in human diabetic patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Sanford Research/Usd
Sioux Falls
United States
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Forred, Benjamin J; Neuharth, Skyla; Kim, Dae In et al. (2016) Identification of Redox and Glucose-Dependent Txnip Protein Interactions. Oxid Med Cell Longev 2016:5829063
Rickel, Kirby; Fang, Fang; Tao, Jianning (2016) Molecular genetics of osteosarcoma. Bone :
Kim, Dae In; Jensen, Samuel C; Noble, Kyle A et al. (2016) An improved smaller biotin ligase for BioID proximity labeling. Mol Biol Cell 27:1188-96
White, Katherine A; Hutton, Scott R; Weimer, Jill M et al. (2016) Diet-induced obesity prolongs neuroinflammation and recruits CCR2(+) monocytes to the brain following herpes simplex virus (HSV)-1 latency in mice. Brain Behav Immun 57:68-78
Simpkins, Jessica A; Rickel, Kirby E; Madeo, Marianna et al. (2016) Disruption of a cystine transporter downregulates expression of genes involved in sulfur regulation and cellular respiration. Biol Open 5:689-97
Booze, Michelle L; Hansen, Jason M; Vitiello, Peter F (2016) A novel mouse model for the identification of thioredoxin-1 protein interactions. Free Radic Biol Med 99:533-543
Yao, Qingqing; Liu, Yangxi; Tao, Jianning et al. (2016) Hypoxia-mimicking nanofibrous scaffolds promote endogenous bone regeneration. ACS Appl Mater Interfaces :
Alam, Samer G; Zhang, Qiao; Prasad, Nripesh et al. (2016) The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity. Sci Rep 6:38063
Mdaki, Kennedy S; Larsen, Tricia D; Wachal, Angela L et al. (2016) Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction. Am J Physiol Heart Circ Physiol 310:H681-92
Baack, Michelle L; Puumala, Susan E; Messier, Stephen E et al. (2016) Daily Enteral DHA Supplementation Alleviates Deficiency in Premature Infants. Lipids 51:423-33

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