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Using NOD and Toll-Like Receptor 3 (TLR3) Knockout Mice in Type 1 Diabetes Research. Tiffany Osemwengie. General Type-1 Diabetes Information. Type 1 diabetes mellitus is a chronic autoimmune disease that results in the destruction of the insulin-producing cells in the pancreas.

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using nod and toll like receptor 3 tlr3 knockout mice in type 1 diabetes research

Using NOD and Toll-Like Receptor 3 (TLR3) Knockout Mice in Type 1 Diabetes Research

Tiffany Osemwengie

general type 1 diabetes information
General Type-1 Diabetes Information
  • Type 1 diabetes mellitus is a chronic autoimmune disease that results in the destruction of the insulin-producing cells in the pancreas.
  • The insulin-producing cells are called beta cells
  • The disease often results in complete loss of insulin production in the pancreas
  • Insulin is an essential hormone that is necessary to allow glucose to enter cells to produce energy
  • Also known as insulin-dependent diabetes and juvenile diabetes
symptoms
Symptoms
  • Increased thirst
  • Frequent urination
  • Extreme hunger
  • Weight loss
  • Fatigue
  • Blurred vision
complications of type 1 diabetes
Complications of Type-1 Diabetes
  • Cardiovascular Disease
  • Nerve damage (neuropathy)
  • Kidney damage
  • Eye damage (cataracts and blindness)
  • Foot damage
  • Skin and mouth conditions
  • Osteoporosis
  • Pregnancy complications
  • Hearing problems
treatment
Treatment
  • Fatal if left untreated
  • Insulin Injections
  • Exercising regularly and maintaining a healthy weight
  • Eating healthy foods
  • Monitoring blood sugar
type 1 diabetes research
Type-1 Diabetes Research

Mouse pancreatic islet visualized using immunofluorescent microscopy

nod mice
NOD Mice
  • The non-obese diabetic (NOD) mouse
  • Widely used model of type-1 diabetes mellitus
  • NOD mice spontaneously develop autoimmune insulin-dependent diabetes around the age of 15 weeks
  • The strain was first developed at the Shionogi Research Laboratories in Aburahi, Japan by Makino and colleagues in 1980
  • They were developed by selecting and inbreeding cataract-prone mice strains
nod mice1
NOD Mice
  • The NOD mice were found to have a mutation in exon 2 of the CTLA-4 gene
  • CTLA-4 plays an important role in regulating the T-cell immune response
  • It is believed that the loss of function in the CTLA-4 gene causes auto-reactive T-cells to attack insulin producing cells, which leads to the development of diabetes in the NOD mice
toll like receptors
Toll-Like Receptors
  • Toll-like receptors (TLRs) are cellular sensors that detect pathogens by recognizing specific pathogen-associated molecular patterns (PAMPs)
  • Found on the surface of macrophages, dendritic cells, and NK cells
  • Can also be found in the membranes of endosomes
  • TLRs were also found to be expressed in human and rodent pancreatic islets
  • Important role in innate immune responses
  • First line of defense against invading pathogens
toll like receptors1
Toll-like Receptors
  • There are 10 different expressed TLR genes in humans, and 13 in mice
  • Each type of TLR recognizes a distinct set of PAMPs
  • When a TLR recognizes a PAMP, a signaling process occurs that leads to the production of cytokines and chemokines
zeynep dogusan et al
ZeynepDogusan et al.
  • It had been known previously that viral infections could contribute to the pathogenesis of type-1 diabetes
  • Viral products, especially double-stranded RNA (dsRNA), affected pancreatic β-cell survival and triggered autoimmunity
  • The mechanism behind the induced β-cell death was unknown
  • The researchers believed that it may have something to do with the TLR3 signaling pathway because TLR3 recognizes viral dsRNA
tlr3 knockout mutants
TLR3 -/- Knockout Mutants
  • The gene for toll-like receptor 3 in mice is located on chromosome 8
  • The gene was disrupted by targeted knockout mutation
  • Exon 1 was replaced through homologous recombination
  • Northern blot analysis detected a truncated transcript in the knockout mutants
  • The mutant transcript does not encode a functional protein
zeynep dogusan et al1
ZeynepDogusan et al.
  • Wild-type and TLR3 -/- knockout mice were used to determine if the TLR3 signaling pathway played a significant role in the development of the autoimmune condition.
  • The pancreatic islets from the mice were isolated and incubated with PICex which is a synthetic dsRNA
  • In another separate in-vivo study using NOD mice, the PICexsynthetic dsRNA was shown to significantly accelerate the development of diabetes in the mice.
zeynep dogusan et al2
ZeynepDogusan et al.
  • The wild-type mice had a much higher percentage of beta cell apoptosis than the TLR3 -/- knockout mice
  • Indication that the detrimental effects of dsRNA on pancreatic β-cells were mediated by the TLR3 signaling pathway
  • Suppression of the TLR3 signaling pathway protects β-cells against dsRNA-induced apoptosis
references
References
  • 1. ZeynepDogusan, MónicaGarcía, Daisy Flamez, Lena Alexopoulou, Michel Goldman, Conny, Gysemans, Chantal Mathieu, Claude Libert, Decio L. Eizirik, and Joanne Rasschaert.Double-Stranded RNA Induces Pancreatic β-Cell Apoptosis by Activation of the Toll-Like Receptor 3 and Interferon Regulatory Factor 3 Pathways Diabetes 2008 57: 1236-1245.
  • 2. RasschaertJ, Ladriere L, Urbain M, Dogusan Z, Katabua B, Sato S, Akira S, Gysemans C, Mathieu C, Eizirik, DL: Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-gamma-induced apoptosis in primary pancreatic beta-cells. J Biol Chem280 :33984 –33991,2005
  • 3. Wen L, Peng J, Li Z, Wong, FS: The effect of innate immunity on autoimmune diabetes and the expression of toll-like receptors on pancreatic islets. Journal of Immunology 172 :3173 –3180,2004