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Searching for innovative biological drugs
Published on Jun 28, 201973 Views
Noncommunicable diseases (NCDs), also known as chronic diseases, tend to be of long duration and are the result of a combination of genetic, physiological, environmental and behavioral factors. The ma
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Chapter list
Searching for innovative biological drugs00:00
The tremendous burden of cardiovascular disorders03:57
Time line showing the development of drugs against heart failure05:27
Biotherapeutics06:24
Biotherapeutics for myocardial ischemia and heart failure07:56
Cytokines and growth factors12:34
Can we select for cardioprotective factors in vivo?13:18
Gene transfer using Adeno-Associated Virus (AAV) vectors14:08
FunSel for the in vivo selection of factors protecting against myocardial infarction - 117:18
AAV arrayed, barcoded libraries18:54
FunSel for the in vivo selection of factors protecting against myocardial infarction - 220:25
AAV9-Ghrelin preserves myocardial function after infarction - 121:26
Ghrelin22:51
AAV9-Ghrelin preserves myocardial function after infarction - 223:32
Ghrelin is a power inducer of autophagy and mitophagy24:19
Cytokines that mediate cardiac engraftment of cells?26:24
FunSel for the selection of cytokines inducing cardiac retention of stem cells26:49
FunSel for the selection of cytokines sustaining BM-MSC engraftment28:24
BM-MSCs treated with Cardiotrophin-128:30
Cardiotrophin 1 induces expression of FAK in BM-MSCs29:09
1 h CTF 1 treatment30:06
CTF 1 h 5 ng30:08
FunSel for the in vivo selection of factors protecting pancreas β-cells30:10
The holy grail of cardiac regeneration31:27
The mammalian heart stops regenerating early after birth31:55
Cardiomyocytes stop proliferating after birth - 132:59
The Oxygen - Rich Postnatal Environment34:55
Cardiomyocytes stop proliferating after birth - 235:47
Regulatory T cells (T-regs) are expanded during pregnancy36:01
Non immunological functions of Tregs37:14
Paracrine effect37:52
Is really the adult heart a postmitotic organ?41:12
Regenerative potential of Ambystoma mexicanum (Axolotl)41:57
Several species other than mammals regenerate the heart42:58
Heart Regeneration in Zebrafish43:20
Transient Regenerative Potential44:32
Functional cardiac tissue created by neonatal cardiomyocytes45:20
New Hypotheses46:04
Carbon dating of cardiomyocytes in human hearts47:04
Screening for cardiomyocyte proliferation using a library of microRNA mimics50:19
40 human miRNAs increase both rat and mouse cardiomyocyte proliferation - 151:31
40 human miRNAs increase both rat and mouse cardiomyocyte proliferation - 252:57
miRNAs increasing myocardial proliferation in vivo – newborn rat heart - 153:27
miRNAs increasing myocardial proliferation in vivo – newborn rat heart - 253:33
miRNAs increasing CM proliferation in vivo53:51
miR-590 and miR-199a preserve myocardial function after MI54:05
miR-590 and miR-199a markedly reduce infarct size55:07
Mechanisms?55:28
Identification of miR-590-3p and miR-199a-3p target genes55:29
Among the 641 genes downregulated by miR-590-3 and miR-199a-3p there are55:56
Identification of miR-590-3p and miR-199a-3p target genes56:28
Identification of miR-590 and miR-199a target genes by deep sequencing56:40
miRNAs promoting cardiomyocyte proliferation activate YAP-induced transcription57:09
Letters57:30
Letter57:59
Effect in human cardiomyocytes?58:01
Effect of selected miRNAs on the proliferation of human ES cell-derived cardiomyocytes58:22
Human fetal cardiomyocyte proliferation - 158:56
Human fetal cardiomyocyte proliferation - 259:29
Human adult cardiomyocytes59:34
Human adult cardiomyocytes replicating DNA01:00:42
Effect in large animals?01:00:51
LAD Occlusion01:01:01
Reduce infarct size01:01:46
4 weeks after MI01:02:53
Infarct/fibrosis area - 101:04:11
Infarct/fibrosis area - 201:04:34
Infarct/fibrosis area - 301:05:04
Sudden cardiac death of AAV6- miR-199a-treated pigs01:05:18
Death of pig#66 at 8 weeks01:05:58
Small cell Hematoxylin Eosin clusters in hearts - 101:06:53
Small cell Hematoxylin Eosin clusters in hearts - 201:07:12
Small cell Hematoxylin Eosin clusters in hearts - 301:07:22
Small cell Hematoxylin Eosin clusters in hearts - 401:07:36
Small cell Hematoxylin Eosin clusters in hearts - 501:07:38
Cell Stem Cell01:08:07
Delivery?01:08:11
Prolonged effect of miRNA mimics after intra-cardiac injection01:08:42
miRNA mimics stimulate myocardial repair after MI01:09:23
Circulation Research01:09:47
Fibrotic diseases contribute to almost 50% of deaths worldwide01:10:08
Drug repurposing01:10:58
The use of genetically modified reporter animals01:11:46
SMA-RFP, COLL-EGFP mice01:12:31
High Throughput screening for FDA - 101:13:31
High Throughput screening for FDA - 201:13:34
Five top drugs inhibiting myofibroblast activation01:13:51
Haloperidol inhibit fibroblast migration and contraction force01:14:01
Fibroblasts do not express the Drd2 receptor01:14:20
Sigmar1 mediates the activity of Haloperidol in fibroblasts01:14:46
Haloperidol does not act on the canonical TGFb pathway01:14:49
Haloperidol increases intracellular calcium similar to known inducers of ER stress01:14:50
Haloperidol induces a mild ER stress01:14:53
Myofibroblast inhibition by Haloperidol requires the Notch pathway01:14:55
Haloperidol inhibits myofibroblast activation after myocardial infarction01:14:57
Haloperidol inhibits lung fibrosis01:15:12
Haloperidol inhibits cancer-associated fibroblasts (CAFs) and tumor growth01:15:28
Haloperidol inhibits myofibroblast activation01:15:29
Intereg - 101:16:05
Intereg - 201:16:12
Data Processing of Unknown Substances01:16:25
Dopamine effectively inhibits myofibroblast activation in vitro01:17:05
Dopamine effectively inhibits myofibroblast activation in vivo01:17:17
Collaborations01:17:23
Thanks01:17:32