Summary
This research project aims to investigate how mitochondrial DNA (mtDNA) leakage promotes inflammation and intervertebral disc degeneration (IDD), with the goal of identifying novel therapeutic targets for low back pain.
mitochondrial DNA leakage promotes inflammation and intervertebral disc degeneration
US · IL
NIH
grant
awarded
#nih-1R01AR086165-01
What they want
The study hypothesizes that oxidative damage to mtDNA leads to its fragmentation and escape through the mitochondrial permeability transition pore (mPTP) into the cytosol, inducing sterile chronic inflammation and promoting IDD. Key questions to be addressed include: (1) Does oxidative damage to mtDNA result in its fragmentation and escape from mitochondria? (2) What is the mechanism of escape of mtDNA? (3) Does mtDNA escape induce inflammation in the IVD? (4) What is the mechanism of mtDNA sensing in IVDs? The overall goal is to examine the impact of mtDNA leakage on inflammation and identify novel therapeutic targets for the management of IDD.
Deliverables
- Understanding if oxidative damage to mtDNA results in its fragmentation and escape from mitochondria
- Elucidating the mechanism of mtDNA escape
- Determining if mtDNA escape induces inflammation in the IVD
- Identifying the mechanism of mtDNA sensing in IVDs
- Identification of novel therapeutic targets for the management of IDD
Technical requirements
- In vitro and in vivo approaches
- Use of isolated disc cells from human surgical samples
- Use of isolated disc cells from mouse discs
- Organotypic cultures of functional spine units (FSU) from mice
- Multiple mouse models, including mtDNA polymerase gamma (PolgA) proofreading mutant, cyclophilin D (CypD) knockout (KO), and Sting KO mice
- Disc needle puncture surgery (NPS) on caudal discs of mice to induce IDD
- Investigation of sex bias in disease pathology using both males and females in all in vivo studies
