1. Ourania Chatzidoukaki
The functional link between the DNA damage and innate immune responses in macrophages
Summer school-Chromatin3D
Heraklion, 1st October2016
In our lab, we focus our studies on Nucleotide Excision Repair, a highly conserved pathway, that removes DNA-helix distorting lesions caused by UV light.
Ourania Chatzidoukaki
Garinis Lab

2. DNA:
the unit that carries the genetic information and transmits it into the progeny.
DNA is an iinformation storage macromolecule that contains whatever is necessary for the growth, maintainanice and function of a living organism. And what is really important is that this kind of information should tranferred intact to the progeny.

3. The DNA damage signaling
DNA damage agents
Cellular metabolism
UV light
Ionizing radiation
Chemicals
Replication errors
The DNA damage signaling
can lead to
chronic inflammation
However there are a couple of factors that can destroy its structure. More specifically these dna damage agents can be uv ight, ionized radiation, chemicals, replication errors and so on. Recently it has been shown in my lab that dna damage can induce inflammation. This happens because dna damage agent can induce or interact with proinflammatory genes.

4. Chronic inflammation
Cardiovascular diseases
Neurological disorders
Metabolic disorder complications
Cancer
Diabetic complications
Bone, skeletal, muscular diseases
A couple of years ago inflammation has started to gain popularity. In fact a times cover point out the crosstalk between inflammation and various disorders. In fact inflammation is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. Indeed chronic inflammation can lead to neurological disorders….

5. Should we care about the mechanism of DNA damage induced inflammation?

6. Aicardi-Goutières syndrome
Trichothiodystrophy
Cockayne syndrome
similar
Neuropathology
and
type I IFN immune responses
The significance lies in the similarity of patients symptoms
Thrichothiodystrophy:is an autosomal recessive inherited disorder characterised by brittle hair and intellectual impairment. 
Cockayne syndrome:  also called Neill-Dingwall syndrome, is a rare fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging
Aicardi-Goutieres syndrome:hich is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodeve

7. Ercc1 -/- express pro- inflammatory genes
Garinis et al., Nat Cell Biol 2008

8. Innate immune response
Aim
Metabolism
Innate immune response
and inflammation
DDR
Disorders
DNA damage
Ageing
How ?
Cancer

9. How are we going to tackle this problem?

10. Bone marrow differentiation with GM-CSF
System
Bone Marrow derived Macrophages isolation
Day 1
Day 1-7
Bone marrow differentiation with GM-CSF
Bone Marrow
BMDMs
Mouse models
Ercc1-/-
Xpa-/-
Xpc-/-
Csbm/m
C57BL/6
Treatments
Mitomycin C
(10 μg/μl)
ATRi (10 μM)
ATMi (10 μM)
H2O2
UV (20kJ)

11. Techniques
Cell cultures
Imaging
Proteomics

12. Result
1. Knowledge
2. Application
Inhibitor

13. Live Longer, Live Healthier
I believe that the take home message is that we should manage to live to live healthier and long and this would be achieved only investing in science
Thank you very much