This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It has been demonstrated an important role of ?1AR signaling in regulation of cardiac myocytes proliferation during the fetal and early postnatal period. We have also demonstrated a constitutively elevated level of signaling of PI3 kinase/P70 ribosomal protein S6 kinase activity (p70 S6K) pathway during the proliferative period of cardiac growth. The dogma of terminal differentiation and absence of cardiomyocytes division in adulthood has been recently challenged. Using unique and well-established stem cell arming strategy, our recent study revealed that intravenously infusion of armed lin-c-kit+ stem cells markedly restored myocardial ventricular function and prevention of cardiac remodeling, which was associated with increase of angiogenesis as well as reduction myocardial apoptosis in infarcted myocardium. Deletion of Akt-1 of stem cells, the known downstream target of ?1AR /PI3 Kinase signaling, completely eliminated the beneficial effect of stem cells infused in infarcted myocardium, demonstrating a crucial role of Akt-1 in mediating stem cells to produce regenerative capacity. It remains known how these components of this unique signaling mediate the myocardial regeneration. We will examine these questions using a combination of genetically modified animals with overexpression of PI3 kinase p110 alpha, stem cells targeted to antigens expressed by injured myocardium, the assessment of cardiac function and biochemical and genetic studies of regenerated cardiomyocytes.
Our specific aims are: 1) Using well-established stem cell arming strategy and myocardial infarction models, we will compare cardiac functional restoration in the damaged heart receiving Lin-c-kit /PI3K-p110 +/+ stem cells with hearts receiving the wild type stem cells;2) we will examine the impact of Lin-c-kit stem cells over-expressing PI3K-p110 alpha on newly regenerated myocyte and angiogenesis;3) By taking advantage of unique tTA system in combination with the in vivo condition, we will attempt to define the contribution of the cell fusion to myocardial regeneration and functional restoration and, We will assess whether the PI3K-Akt-1 working model will orchestrate myocardial regeneration following stem cells administration. PI3K+/+-Akt 1-/- Lin-c-kit+stem cells will be generated from double transgenic mice by crossing PI3K+/+ and Akt 1-/- mouse lines.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR018728-09
Application #
8360540
Study Section
Special Emphasis Panel (ZRR1-RI-6 (01))
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
9
Fiscal Year
2011
Total Cost
$220,974
Indirect Cost
Name
Women and Infants Hospital-Rhode Island
Department
Type
DUNS #
069851913
City
Providence
State
RI
Country
United States
Zip Code
02905
Patra, Aparna; Chen, Xiaodi; Sadowska, Grazyna B et al. (2017) Neutralizing anti-interleukin-1? antibodies reduce ischemia-related interleukin-1? transport across the blood-brain barrier in fetal sheep. Neuroscience 346:113-125
Taggart, Allison J; Lin, Chien-Ling; Shrestha, Barsha et al. (2017) Large-scale analysis of branchpoint usage across species and cell lines. Genome Res 27:639-649
Monahan, Zachary; Ryan, Veronica H; Janke, Abigail M et al. (2017) Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J 36:2951-2967
Kao, Hung-Teh; Ryoo, Kanghyun; Lin, Albert et al. (2017) Synapsins regulate brain-derived neurotrophic factor-mediated synaptic potentiation and axon elongation by acting on membrane rafts. Eur J Neurosci 45:1085-1101
Kalkunte, Satyan; Huang, Zheping; Lippe, Eliana et al. (2017) Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects. Sci Rep 7:39885
Conicella, Alexander E; Zerze, Gül H; Mittal, Jeetain et al. (2016) ALS Mutations Disrupt Phase Separation Mediated by ?-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure 24:1537-49
Yilmaz, Atilgan; Kattamuri, Chandramohan; Ozdeslik, Rana N et al. (2016) MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells. Sci Signal 9:ra87
Uzun, Alper; Schuster, Jessica; McGonnigal, Bethany et al. (2016) Targeted Sequencing and Meta-Analysis of Preterm Birth. PLoS One 11:e0155021
Zhang, Jiyong; Klufas, Daniel; Manalo, Karina et al. (2016) HMGB1 Translocation After Ischemia in the Ovine Fetal Brain. J Neuropathol Exp Neurol 75:527-38
Cheng, Shi-Bin; Nakashima, Akitoshi; Sharma, Surendra (2016) Understanding Pre-Eclampsia Using Alzheimer's Etiology: An Intriguing Viewpoint. Am J Reprod Immunol 75:372-81

Showing the most recent 10 out of 164 publications