ORCID Profile
0000-0001-5843-8564
Current Organisations
Stanford University
,
University of California
,
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
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Publications
Translational strategies and challenges in regenerative medicine
Publisher: Springer Science and Business Media LLC
Date: 08-2014
DOI: 10.1038/NM.3627
Abstract: The scientific community is currently witnessing substantial strides in understanding stem cell biology in humans however, major disappointments in translating this knowledge into medical therapies are flooding the field as well. Despite these setbacks, investigators are determined to better understand the caveats of regeneration, so that major pathways of repair and regrowth can be exploited in treating aged and diseased tissues. Last year, in an effort to contribute to this burgeoning field, Nature Medicine, in collaboration with the Volkswagen Foundation, organized a meeting with a panel of experts in regenerative medicine to identify the most pressing challenges, as well as the crucial strategies and stem cell concepts that can best help advance the translational regenerative field. Here some experts who participated in the meeting provide an outlook at some of those key issues and concepts.
Altered caveolin-3 expression disrupts PI(3) kinase signaling leading to death of cultured muscle cells
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.YEXCR.2006.05.010
Abstract: Caveolae and their coat proteins, caveolins, co-ordinate multiple signaling pathways. Caveolin-3 is a muscle-specific caveolin isoform that is deficient in limb girdle muscular dystrophy type 1 C (LGMD1C). Paradoxically, overexpression of this protein also causes muscle degeneration in vivo. We hypothesize that altered membrane expression of caveolin-3 in muscle cells causes a degenerative phenotype by disrupting the co-ordination of signaling pathways that are critical to the maintenance of cell survival. Here, we show for the first time that, in normal muscle cells subjected to oxidative stress, the phosphatidylinositol (3) kinase (PI(3) kinase)-associated proteins PDK1 and Akt associate with caveolae where they bind to caveolin-3, and that normal activation of this pathway promotes cell survival. Either increased or decreased expression of caveolin-3 at the membrane caused an increased susceptibility to oxidative stress, and myotube survival was markedly improved by PI(3) kinase inhibition. This occurred concomitantly with altered phosphorylation of the pro-apoptotic proteins GSK3beta and Bad, despite normal levels of Akt activation. Taken together, our results demonstrate that altered caveolin-3 expression can change the outcome of PI(3) kinase activation from cell survival to cell death. These findings indicate that normal expression and localization of caveolin-3 are required to appropriately co-ordinate PI(3) kinase/Akt-mediated cell survival signaling, and suggest that this pathway may be an effective therapeutic target for the treatment of muscular dystrophies associated with caveolin-3 mutations.
Bioengineered Viral Platform for Intramuscular Passive Vaccine Delivery to Human Skeletal Muscle
Publisher: Elsevier BV
Date: 09-2018
Notch-Mediated Restoration of Regenerative Potential to Aged Muscle
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-11-2003
Abstract: A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age.
Related Organisations
Eli And Edythe Broad Center Of Regenerative Medicine And Stem Cell Research, University Of California Los Angeles
Location: No location found
Eli And Edythe Broad Center Of Regenerative Medicine And Stem Cell Research, University Of California Los Angeles
Location: United States of America
Related Funding Activities
No related grants have been discovered for Thomas Rando.