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Molecular Mechanisms of Heart Disease

Research Approaches
methods
Immunocytofluorescence confocal microscopy shows that the new drug candidate, code named 147, selectively activates the protective ATF6 target genes, catalase (Cat) and Grp78 in wild type (WT) mouse hearts, but not in the hearts of mice where ATF6 was selectively knocked out from cardiac myocytes (ATF6 cKO). Blackwood et al. (2018) Nat Commun., in press.

Research Topics

ATF6 and Cardiac Growth
ER stress dysregulates ER proteostasis, which activates the transcription factor, ATF6, an inducer of genes that enhance protein folding and restore proteostasis. Due to increased protein synthesis, it is possible that protein folding and, thus, ER proteostasis are challenged during cardiac myocyte growth....read more
atf6 and cardic growth


Pharmacologic Activation of ATF6
Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. In recent research done in the Glembotski lab...read more
atf6_activation


A Molecular Social Network- Cardiokine Secretion
One of the projects in the Glembotski lab involves identifying proteins secreted by the heart, determining what their functions are in myocardial function, as well as regenerating damaged heart tissue, and elucidating the mechanisms of their secretion. Communication between individuals of a society is essential for effective functioning of the whole. Tissues, organs and organisms are...read more
cardiokine


ER Stress and the Unfolded Protein Response- Protein Quality Control in the Heart
Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to cardiovascular disease. In large part, the misfolding of proteins takes place during....read more
stress


Regenerative Medicine and Stem Cells
Proteins secreted by the heart are called cardiokines. After secretion, cardiokines, such as cytokines, growth promoters and stem cell homing factors, can reduce ischemic damage, as well as enhancing stem cell survival and engraftment. But ischemia impairs protein folding and secretion, and negatively impacts stem cell-mediated regeneration. However, we discovered a secretion process that resists this inhibition...read more
regeneration


Genomics and Gene Therapy
One of the main goals of research in the Glembotski lab is to develop prototypes of therapies that could be used as platforms for the development of novel treatments for heart disease. One such prototype involves the selective delivery of cardioprotective genes to the heart using an adenovirus-associated (AAV) gene therapy approach. In our studies of secretion, ER stress and stem cells in...read more
gene


Proteomics and Protein Therapy
In efforts to develop novel therapies of treating heart disease, research in the Glembotski lab is focused on how to deliver cardioprotective agents to the heart without leaving a genetic footprint. One method to accomplish this is to deliver protective proteins directly to the heart using state-of-the-art protein formulation and transduction methods. One such method involves combining ...read more
protein