Pathology of Pancreatic Β-Cell and Diabetes in Premature Aging Cisd2 Knockout and Naturally Aging Wild-Type Mice

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Aging which affects all organ systems is one of the most complex phenotypes in biomedical sciences. Application of genetically modified mouse models will help elucidate the genetic pathways of human aging. CISD2 is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q where a genetic component for longevity maps. Recently, the CISD2 gene has been identified as the second causative gene associated with Wolfram syndrome (WFS, MIM 222300), patients with a homozygous mutation of the CISD2 gene have been classified as WFS2 (MIM 604928). WFS is highly variable in its clinical manifestations, which include diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Our group had previously generated Cisd2 knockout mice and demonstrates for the first time that CISD2 is involved in mammalian lifespan control. Cisd2 deficiency in mice causes mitochondrial outer membrane breakdown and dysfunction accompanied by autophagic cell death and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Thus, this Cisd2 knockout mouse provides an animal model for mechanistic investigation of Cisd2 protein function and will help with a pathophysiological understanding of aging . Degenerations of nervous and muscle systems, which usually exacerbates with age, are the two major phenotypic effects associated with aging. Importantly, Cisd2 knockout mice exhibit a progressive neurodegenerative phenotype that includes optic nerve defects. Regarding glucose homeostasis, we found that Cisd2 knockout mice display a milder phenotype, namely, impaired glucose tolerance and decreased insulin secretion. Recently, our results showed that Cisd2 deficiency in mice causes pancreatic β-cell mitochondrial outer membrane breakdown and dysfunction accompanied by significantβ-cell autophagy. However, the damaged mitochondria induce autophagy as a cytoprotective response to eliminate the dysfunctional organelle, or excessive autophagy may cause pancreatic β-cell to death, that is accompanied by decreased insulin secretion, impaired glucose tolerance, and finally induce diabetes needs to be thoroughly clarified. In this grant, we will introduce the Cisd2 mutant allele into DBA/2 or 129/Sv diabetes-prone strains of mice (generation of congenic strains of Cisd2 knockout mice with a diabetessensitive background by backcrossing into the DBA/2 or 129/Sv inbred mice), which may contain genetic modifier(s) that increase susceptibility to diabetes. We propose to systematically examine the ultrastructural alternations of pancreatic β -cell using transmission electron microscope (TEM) during naturally aging process of the wild-type mice and compare with those observed in the premature Cisd2 knockout mice and the diabetes-prone congenic strains of mice. In addition, we will perform biochemical characterization of the mitochondrial functions in pancreatic β -cell to correlate the morphological evidence of TEM. We anticipate that we will have a complete panel of ultrastructural database and basic biochemical results within three years. These investigations will help evaluate the feasibility of using Cisd2 mutant mice as an animal model for screening of agents associated with pancreatic β-cell disorder and might eventually provide clues about how to slow the age-associated diabetes process.

Project IDs

Project ID:PC10008-0756
External Project ID:NSC100-2320-B182-031
StatusFinished
Effective start/end date01/08/1131/07/12

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