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David GutsteinClinical Associate Professor, Department of Medicine
NYU Cardiac Exercise / Stress Lab
Intercellular communication in the heart is mediated by gap junctions, channels that are critical for normal heart morphogenesis and for cardiac conduction. Although gap junctions play a vital role in cardiac physiology and are known to be dysregulated in disease, no available therapeutics are presently targeted to them. To investigate pathways that regulate and are regulated by gap junctions, Dr. Gutstein studies two specific areas of gap junction biology. First, Dr. Gutstein uses developmental models to investigate the effect of gap junctions on cardiac development. Germline loss of connexin43 (Cx43), the predominant cardiac gap junction component protein, is known to cause right ventricular outflow tract malformations, perinatal death and coronary anomalies. Research in the Gutstein laboratory suggests that the Cx43-null coronary phenotype may result from loss of Cx43 specifically in the neural crest population. However, the mechanisms by which Cx43 regulates the contribution of the neural crest to coronary development are not known. Ongoing studies in the laboratory are directed at identifying and characterizing how gap junctions may influence coronary patterning. The second area of interest in Dr. Gutstein's laboratory is the study of gap junction remodeling (GJR). Structural GJR is an abnormal localization of connexin protein along the sarcolemma of the myocyte and/or a generalized down-regulation of gap junction protein. The process of GJR has been strongly associated with arrhythmic cardiac conditions such as myocardial hypertrophy, infarction and heart failure. Dr. Gutstein has developed a novel method to induce GJR in the mouse by pacing at rates just over that of sinus rhythm for six hours. This is the first such method for use in the mouse that does not cause myocardial injury, hypertrophy or a decrease in cardiac function. Studies in the laboratory use this model to study the mechanisms by which GJR develops and the physiologic effects of GJR in the heart.
Dr. Gutstein's research interests revolve around the role of intercellular communication in cardiac development and function. Gap junctions are specialized intercellular channels that allow the passage of ions and small molecules between cells. Connexin43 (Cx43), the most abundant gap junction protein in the heart, plays a critical role in heart development, cardiac function and conduction. Understanding developmental pathways and mechanisms in the embryonic heart may provide insight into the pathophysiology of heart failure, a process often associated with recapitulation of fetal gene expression patterns.
Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells
Taniguchi Ishikawa, Eri; Gonzalez-Nieto, Daniel; Ghiaur, Gabriel; Dunn, Susan K; Ficker, Ashley M; Murali, Bhuvana; Madhu, Malav; Gutstein, David E; Fishman, Glenn I; Barrio, Luis C; Cancelas, Jose A. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2012 Jun 05;109(23):9071-9076 (169558)
Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors
Gonzalez-Nieto, Daniel; Li, Lina; Kohler, Anja; Ghiaur, Gabriel; Ishikawa, Eri; Sengupta, Amitava; Madhu, Malav; Arnett, Jorden L; Santho, Rebecca A; Dunn, Susan K; Fishman, Glenn I; Gutstein, David E; Civitelli, Roberto; Barrio, Luis C; Gunzer, Matthias; Cancelas, Jose A. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012 May 31;119(22):5144-5154 (170679)
Connexin-43 Expression Regulates the Migration of Hematopoietic Stem Cells and Progenitors towards and From Bone Marrow
Gonzalez-Nieto, D; Chang, KH; Koehler, A; Arnett, J; Dunn, S; Li, L; Ghiaur, G; Sengupta, A; Fishman, G; Gutstein, D; Civitelli, R; Barrio, L; Gunzer, M; Cancelas, J. Connexin-43 Expression Regulates the Migration of Hematopoietic Stem Cells and Progenitors towards and From Bone Marrow [Meeting Abstract]. Blood. 2009 NOV 20 ;114(22):234-234 (109972)
Connexin-43 Regulates the Cell Cycle Entry of Hematopoietic Stem Cells within the Stem Cell Niche
Gonzalez-Nieto, D; Ghiaur, G; Li, L; Arnett, J; Dunn, S; Fishman, G; Gutstein, D; Civitelli, R; Cancelas, J. Connexin-43 Regulates the Cell Cycle Entry of Hematopoietic Stem Cells within the Stem Cell Niche [Meeting Abstract]. Blood. 2009 NOV 20 ;114(22):602-603 (109978)
Identification of binding partners for the cytoplasmic loop of connexin43: a novel interaction with beta-tubulin
Kang, Eunice Y; Ponzio, Marc; Gupta, Pritha P; Liu, Fangyu; Butensky, Adam; Gutstein, David E. Identification of binding partners for the cytoplasmic loop of connexin43: a novel interaction with beta-tubulin. Cell communication & adhesion. 2009 ;15(5-6):397-406 (138363)