2012-2.2.2-1: Integrative systems biology and comparative genomics for studying

human ageing and most common age-related conditions

Donetsk National Medical University Department of Histology, Cytology and Embryology

Department of Propaedeutics of Internal Medicine Institute of Urgent and Recovery Surgery

Laboratory of Fundamental Research S. Fyodorov Eye Microsurgery Federal State Institution, Moscow, Russian Federation)

PARTNERS:

Drugs, nutrients, l ifestyle

Aging is programmed or

simply determined by

interactions between

environmental and

genetic factors

Cellular determinants of ageing

•Insulin/insulin-like growth factor-1 (IGF-1)•Fox-head transcription factors (FOXOs) •Klotho gene•HSP•Antioxidants•Sirtuins•Sestrins

• Reactive oxygen• Mitochondria dysfunction • DNA damage• Telomere attrition• Lysosomal dysfunction• Sress-ER• Proteosome dysfunction

Key mechanisms of development:• Changes of Autonomic innervation:

desympathization, increase sensitivity of target cells to epinephrine, changes in vessels tone regulation;

• Endothelial dysfunction - deficient of NO, decrease of cytoprotection, loss of antiaggregation and barrier function, changes in angiogenesis;

• Dysfunction of specialized cells

• Altered epithelio-mesenchymal interactions (reduced IGF1 and Wnt2; increased TGFβ, ECM hyperproduction)

• Cytokine network disturbance (dendritic cells dysfunction)

Key features:

• blood pressure increase • atherosclerosis• may contribute to myocardial infarction and stroke • limiting adult stem cell life span• wound/ ulcers healing problems • renal / cardiac sclerosis • Immunological ageing

Tissue and organ determinants of ageing

Vascular Endothelium

PG I2

PG E2

NО

Endothelin-1ACEAngII

TGFβ

Endothelial dysfunction

Specialized cells (pigment epithelium)

NОPEDFEGFILGF

bFGFVEGF

TGFβ

Pigment epithelium dysfunction

Connective tissue cells

Extracellular matrix hyperproduction

PRELIMINARY

STUDY

Published: “Pathology of eye at pseudoexfolliation syndrome” – M., 2010. – 156 p.

Method of early diagnostics of glaucoma at pseudoexfoliation syndrome (patent of Russia №2010116856)

The pathogenesis of open-angle glaucoma with pseudoexfoliationsyndrome // Ophthalmology. – 2010. – Vol. 3. – p. 106.

Integrative model for early diagnostics and prognosis

Approach for analysis

Morphology

Immunocytochemistry

Morphology

Immunocytochemistry

Verification

•Disease stage/degree

•Kinetics of cells

•Cellular types and activities

•Chemical composition of matrix

•Functional reserve

Clinical symptoms

Functional loading tests

Clinical symptoms

Functional loading tests

Inhibitor analysis

(blood cells as model)

Inhibitor analysis

(blood cells as model)

Genes polymorphism

microRNA

Genes polymorphism

microRNA

Integrative analysis ofIndividual reactivity

•Receptors sensitivity •Intracellular signaling

(Phospholipases, Ca2+, eNOS, Adenilyl Cyclese, Phosphodiesterases,

Protein Kinases A, C, G)

CELLULAR AND MOLECULAR TARGETS

Preliminary results: diabetes mell i tus. Complications Prognosis of diabetic wound healing

iNOS

р38-МАРК AGEsNADPН-oxidase

ROS Са2+

↑↑↑↑↑↑ПкСПкС CGMPCGMP - - PkGPkGcAMPcAMP - - PkPkАА

0

60

120

180

240

300

К 1 day 3 days 10 days 20 days

Arginase iNOS

Endothelial dysfunction

platelets

Aggregation

NO

Arachidonic acid metabolites

Cytokines

Violation of microcirculation, release of 5-HN, TXA2 etc

Induce adhesion

-Adreno- and adenosine receptors sensitivity

AT1 receptors (X1)

-Protein kinase C hyperstimulation

- ↓ eNOS / PDE5 (X2)

Y= -0,03 × Х1-0,082 × Х2-1,652

Ycrit=0,515

Y= -0,032 ×X 1 -0 ,0029 × X 2 + 1,630

Y сrit=0,281

CD CD 3131 ++

αα -SMA -SMA

CD 68CD 68 ++

MonocytesMonocytes PlateletsPlatelets

Published in : Clinical surgery . - 2009, 2010. Physiological Journal, 2011.

Thank you for attention