Mechanisms enhancing functional coupling between native and embryonic stem cell d
Principal Investigator: Karen Maass
Abstract: DESCRIPTION (provided by applicant): The goal of this application is to obtain funding through the "Restoration of New Investigator Pilot Projects Adversely Affected by Hurricane Sandy" opportunity. In October 2012, I had collected strong preliminary data and was preparing an R01 application for the June 2013 deadline. My research was seriously impacted by the after-effects of Super-storm Sandy. My losses include a colony of connexin43 (gap junction) mutant mice, generated as recipients for cell-transplantation studies, a breeding colony of rats, as well as precious frozen cell lysates and tissue samples awaiting molecular and histological analyses. Experiments proposed in this application will restore pilot project data towards a competitive grant submission, anticipated for summer/fall 2014. My long-term research interest is improving the therapeutic use of pluripotent stem cells (PSC) for heart diseases. PSC allow gene manipulation and can be differentiated into functional heart muscle cells in the dish. Already, PSC are being used for personalized medicine approaches, and PSC will be a suitable source for autologous cell replacement therapy in the future. To be seriously contemplated for therapeutic applications, however, several challenges remain, including long-term survival and functional engraftment of transplanted cells. Engraftment of cells is enhanced by intercellular connections, or cell-cell contacts, formed by specialized proteins. Cell contacts provide structural tissue support (mechanical junctions: adherens junctions;desmosomes) and allow fast impulse propagation and the synchronous contraction of the heart muscle (electrical junctions: gap junction channels). Indeed, transplantation of cardiomyocytes derived from PSC lacking the gap junction protein connexin43, lead to increased arrhythmogenesis in mice. Our preliminary data demonstrate that stem cell derived cardiomyocytes form very few functional gap junction contacts with native cardiomyocytes. The overarching hypothesis of this proposal is that an increase in gap junction channel formation and function will improve the therapeutic efficacy of stem cell derived cardiomyocytes. I will employ three different approaches to test this hypothesis. Based on preliminary data, I will investigate how the formin protein Daam1 enhances gap junction formation. Further, I will analyze the influence of forced gap junction channel formation for cell engraftment using PSC expressing a mutant gap junction channel, K258stop. Additionally I will use a high throughput screen to identify small molecules regulating gap junction expression in stem cell derived cardiomyocytes. While experiments proposed in this study will elucidate ways to enhance the formation of gap junctions in stem cell derived cardiomyocytes, the mechanisms identified might very well also be applicable and therapeutically relevant to the treatment of cardiac diseases related to changes in gap junction formation.
Funding Period: 2013-09-26 - 2015-09-25
more information: NIH RePORT
- The Shelf Live Evaluation of Investigational Dosage FormsJonathan White; Fiscal Year: 2013..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
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- Neural Mechanisms of ItchROBERT H LA MOTTE; Fiscal Year: 2013..abstract_text> ..
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- Novel Therapies for Muco-Obstructive Lung DiseasesRICHARD CHARLES BOUCHER; Fiscal Year: 2013..abstract_text> ..
- Genetic enhancement of cardiac repair with adult stem cellsLoren J Field; Fiscal Year: 2013..Ultimately these approaches might be useful to reconstitute myocardial mass following cardiac injury. ..
- Connexin Distribution in Physiological Versus Pathological Cardiac HypertrophyMichael R Zile; Fiscal Year: 2013..pathological hypertrophy, with ex- tensively characterized cytoskeletal properties in each setting. ..
- Mechanisms of Atherogenesis in Insulin ResistanceIRA A TABAS; Fiscal Year: 2013..End of Abstract) ..
- Center for Neuroplasticity at the University of Puerto RicoSteven N Treistman; Fiscal Year: 2013..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
- Advancing Experimental Models to Study Intercellular Crosstalk of Cardiac CellsUlrike Mende; Fiscal Year: 2013..Furthermore, we anticipate that the models that will be developed and the insights gained in this project will facilitate research on intercellular crosstalk between other cell types in the cardiac field and beyond. ..
- Blood Pressure Regulation: Novel Roles for the KidneyPablo A Ortiz; Fiscal Year: 2013..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
- Cell-Based Cardiac RepairCharles E Murry; Fiscal Year: 2013..These experiments will advance our understanding of human heart development and make clinical trials of heart regeneration more feasible. ..
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- Integration and Arrhythmia Suppression with hESC-Derived Cardiomyocyte GraftsMICHAEL ALAN LAFLAMME; Fiscal Year: 2013..Finally, in Aim 3, we will use in vitro models to develop Wnt5a-mediated chemotaxis as a complementary strategy to improve the integration of hESC-CM grafts. ..
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