This document summarizes research on integrating systems biology and comparative genomics to study human aging and age-related conditions. It discusses several key cellular and tissue determinants of aging, including insulin/IGF-1 signaling, FOXO transcription factors, Klotho gene, antioxidants, sirtuins, telomere attrition, and mitochondrial dysfunction. It also outlines changes in autonomic innervation, endothelial dysfunction, specialized cell dysfunction, and extracellular matrix alterations that influence tissue and organ aging. Preliminary results on diabetes mellitus complications and prognosis of diabetic wound healing are presented.
Event: Plant and Animal Genomes conference 2012
Speaker: Michel Schneider
The UniProt Knowledgebase consists of two sections, UniProtKB/Swiss-Prot, which contains manually-annotated protein sequence enriched with functional information added by expert human curators, and UniProtKB/TrEMBL, which contains unreviewed records that are enhanced by information provided by automated rule-based annotation systems. The majority of UniProtKB records are based on automatic translation of coding sequences (CDS) provided by submitters at the time of initial deposition to the nucleotide sequence databases. In order to provide the complete proteome of Arabidopsis thaliana, a complementary curation pipeline for import of protein sequences from TAIR has been developed. As the complete genome reannotation proposed in the TAIR10 release contains most of the sequences already in UniProtKB, these existing sequences have to be reconciled with those imported. Around 7% of them have a different gene model and should be checked manually. Based on these comparisons, we improved over 200 of our predicted proteins. In exchange, we provide TAIR with the gene model corrections that we introduce on the bases of our trans-species family annotation. This approach allows identification of data that can be seamlessly transferred from one site to the other and the development of common annotations. With the significant increase in the number of complete genomes sequenced (1001 Arabidopsis cultivars are currently under way!), organization of this data in a convenient way is critical. UniProt have selected a set of “reference proteomes”, including A. thaliana cv. Columbia, which provide broad coverage of the tree of life and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
Prof. Vladimir Khavinson, M.D.,Ph.D.
Director of the St. Petersburg Institute of Bioregulation and Gerontology
Member of the Russian Academy of Sciences
Event: Plant and Animal Genomes conference 2012
Speaker: Michel Schneider
The UniProt Knowledgebase consists of two sections, UniProtKB/Swiss-Prot, which contains manually-annotated protein sequence enriched with functional information added by expert human curators, and UniProtKB/TrEMBL, which contains unreviewed records that are enhanced by information provided by automated rule-based annotation systems. The majority of UniProtKB records are based on automatic translation of coding sequences (CDS) provided by submitters at the time of initial deposition to the nucleotide sequence databases. In order to provide the complete proteome of Arabidopsis thaliana, a complementary curation pipeline for import of protein sequences from TAIR has been developed. As the complete genome reannotation proposed in the TAIR10 release contains most of the sequences already in UniProtKB, these existing sequences have to be reconciled with those imported. Around 7% of them have a different gene model and should be checked manually. Based on these comparisons, we improved over 200 of our predicted proteins. In exchange, we provide TAIR with the gene model corrections that we introduce on the bases of our trans-species family annotation. This approach allows identification of data that can be seamlessly transferred from one site to the other and the development of common annotations. With the significant increase in the number of complete genomes sequenced (1001 Arabidopsis cultivars are currently under way!), organization of this data in a convenient way is critical. UniProt have selected a set of “reference proteomes”, including A. thaliana cv. Columbia, which provide broad coverage of the tree of life and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
Prof. Vladimir Khavinson, M.D.,Ph.D.
Director of the St. Petersburg Institute of Bioregulation and Gerontology
Member of the Russian Academy of Sciences
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
1. 2012-2.2.2-1: Integrative systems biology
and comparative genomics for studying
human ageing and most common age-related
conditions
PARTNERS:
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)
2. Drugs, nutrients, lifestyle
Aging is programmed or
simply determined by
interactions between
environmental and
genetic factors
4. Tissue and organ determinants of
ageing
Key mechanisms of development: Key features:
• Changes of Autonomic innervation: • blood pressure increase
desympathization, increase sensitivity of target
cells to epinephrine, changes in vessels tone • atherosclerosis
regulation; • may contribute to myocardial infarction
• Endothelial dysfunction - deficient of NO, and stroke
decrease of cytoprotection, loss of • limiting adult stem cell life span
antiaggregation and barrier function, changes in • wound/ ulcers healing problems
angiogenesis;
• renal / cardiac sclerosis
• Dysfunction of specialized cells • Immunological ageing
• Altered epithelio-mesenchymal
interactions (reduced IGF1 and Wnt2;
increased TGFβ, ECM hyperproduction)
• Cytokine network disturbance (dendritic
cells dysfunction)
5. P
R
E
L
I Vascular Specialized cells
Connective tissue
M Endothelium cells (pigment epithelium)
I
N PG I2 NО
PEDF
A PG E2
NО EGF
ILGF
R
Y Endothelin-1
ACE bFGF
VEGF
AngII Extracellular matrix
TGFβ TGFβ
hyperproduction
S Pigment
T Endothelial epithelium
U dysfunction dysfunction
D Published: “Pathology of eye at pseudoexfolliation syndrome” – M., 2010. – 156 p.
Y 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.
6. Integrative model for early diagnostics and
prognosis
Approach for analysis
Morphology Inhibitor analysis
Immunocytochemistry (blood cells as model)
Clinical Verification Integrative analysis of Genes
symptoms Individual reactivity polymorphism
•Disease stage/degree
•Kinetics of cells •Receptors sensitivity
Functional •Cellular types and activities microRNA
•Intracellular signaling
loading tests •Chemical composition of
matrix (Phospholipases, Ca2+, eNOS, Adenilyl
Cyclese, Phosphodiesterases,
•Functional reserve Protein Kinases A, C, G)
CELLULAR AND MOLECULAR TARGETS
7. Preliminary results: diabetes mellitus. Complications
Prognosis of diabetic wound healing
Monocytes Platelets
CD 68 + Arginase iNOS Aggregation
300
240 Violation of microcirculation,
platelets
release of 5-HN, TXA2 etc
180
120
Cytokines NO
60 Induce
CD 31 + adhesion
Arachidonic acid metabolites
0
К 1 day 3 days 10 days 20 days
Endothelial dysfunction
NADPН-oxidase р38-МАРК AGEs
-Adreno- and adenosine receptors
sensitivity
ROS iNOS Са2+
AT1 receptors (X1)
-Protein kinase C hyperstimulation
α -SMA cAMP - PkА
PkА ↑↑↑ПкС
↑↑↑ПкС CGMP - PkG
- ↓ eNOS / PDE5 (X2)
Y= -0,032 × X 1 -0,0029 × X 2 + Y= -0,03 × Х1-0,082 × Х2-1,652
1,630
Ycrit=0,515
Published in : Clinical surgeryсrit =0,281 Physiological Journal, 2011.
Y . - 2009, 2010.