12.5 Results of validation study by qRT-PCR
12.5.1 Gene-specific correlation between RT-PCR and microarray results
Thermalcycler PCR for GAPDH and other genes showed a single (peak) product indicating that no false amplification occurred. The expressions of 21 genes were quantified for their respective abundance. The amount of gene was normalized to the housekeeping gene, GAPDH. In most cases, the relative expression determined by real-time RT-PCR quantitation was concordant with the expression determined by gene array analysis. The higher level of concordance was more evident at day 7 (Table 14, Graph 5, Graph 6, Graph 16). How ever one gene showed variations generated by the two methodologies. The gene HSP70 showed up regulation on the RT-PCR analysis in opposition to down regulation shown by the micro array analysis. Since the primers for Real-Time PCR are gene-specific.
It was likely that the cross-hybridzation between the members of the genes could have occurred in the micro array experiment.
Pearsons correlation between the mean values of fold changes for quantitative real-time RT- PCR and micro array analysis at different time points was -0.142 (p-Value 0.550) at for day 1, -0.117 (p-Value = 0.622) for day 3 and 0.559 (p- Value 0.010) for day 7. Among the twenty genes TIMP1, RAC, TRAM1, PRKCD, SRP5, GUSB showed a paired correlation between 5 to 9 (Table 14). Paired t-test between the 9 comparisons did not show statistically significant difference between the the fold changes of microarray and quantitative real-time RT-PCR for the genes in day 1 observation whereas for day 7 and day 3 TIMP1, RAB7, COL1A1, FTL, TRAM1, PRKCD, SRP54, TUBG1, HSPB1, HSP70, GUSB, HMGB1 showed significant differences (Graph 16).
In most cases, quantitative and qualitative expression levels detected by QRT-PCR were consistent and comparable to the microarray expression.
13, Conclusion
1 3 CONCL U SIONS
The results of the current experiment appeared to suggest a dominance of events in the alveolar bone socket over the PDL on root surface.
ALVEOLAR BONE:
1. There were generally higher genetic expressions in alveolar bone compared to the periodontal tissue in both immediate-replanted (favorable outcome) and delayed- replanted (unfavorable outcome) groups.
2. The onset of molecular events in the alveolar bone was almost immediate starting from day 1 in both immediate-replanted and delayed-replanted groups.
3. With one functional group exception, there was no distinct difference in gene expression in both immediate and delayed-replanted groups across the different functional categories.
4. Notably, hormone PTHLH associated with bone resorption was down regulated from day 1 and up regulated from day 3 onwards till the last observation day 7 in the immediate and delayed replantation groups, respectively. Growth factor TGF-β1 promoting proliferation of oteoblastic / ostolytic phenotype was up regulated in both immediate and delayed groups throughout the observation period from day 1 to day 7. Likewise, cell cycle regulation gene PPP2CA implicated in cell proliferation and spreading are up regulated in both immediate and delayed replantation groups throughout the observation period from day 1. Speculatively, these genes expressed in the early phase within the alveolar socket potentially lead to a cascade of molecular events resulting in different healing outcome in the two different groups at a later phase.
PERIODONTAL LIGAMENT
1. There were generally lower genetic expressions in the PDL compared to the alveolar bone in both immediate-replanted (favorable outcome) and delayed-replanted (unfavorable outcome) groups.
2. The onset of molecular events was almost immediate in the immediate replantation group commencing from day 1, while it was delayed till day 3 in the delayed- replanted group.
3. There were distinct differences in gene expression patterns between the immediate- replanted group and the delayed-replanted groups.
4. Apoptotic genes MCL1 and PSEN1 implicated in cell death and delayed onset of angiogenesis were pronouncedly up regulated in the delayed-replanted group but down regulated in the immediate-replanted group from day 1. Similarly, cell adhesion molecules ICAM1, DSG1 and DSG3 essential for maintaining cell integrity were down regulated in delayed group but up regulated in immediate group both from day 1. Cell cycle regulation gene PPP2CA was down regulated in the delayed-replanted group while in the immediate-replanted group, the genetic profile remained status quo at the base line level throughout from day 0 to day 7. These suggest PDL tissue in the delayed-replanted group had been severely stressed, undergo degradation with diminished potential to express genes which modulate regeneration and repair.
14, Future Directions
1 4 FUTU RE DIRE CTI ONS
• Genes that have been screened in this study will be further validated through real-time PCR,
immunohistochemical or in-situ hybridization techniques by focusing on pathways involving the different biological processes presumed to be responsible for the unfavorable outcome seen in delayed replanted tooth.
• Future identification of encoding proteins using proteomics may provide valuable information
and subsequent functional therapeutics strategy for delayed replanted teeth to overcome the adverse outcomes.
• Further understanding and integrating knowledge gathered from genomics, proteomics and,
bioengineering as wel as bioinformatics can facilitate future in development of genetically engineered progenitor cells and aid in regeneration of new periodontal tissue at the replanted wound site.
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