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
External Project ID:NSC100-2320-B182-031
Status | Finished |
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Effective start/end date | 01/08/11 → 31/07/12 |
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