University of Cincinnati Department of Pediatrics

Katherine Yutzey, PhD

Appointment

Professor, University of Cincinnati College of Medicine

Phone

513-636-8340

Fax

513-636-5958

Bio

Visit Dr. Yutzey's Lab Web Site.

Katherine E. Yutzey, PhD, professor, joined the Division of Molecular Cardiovascular Biology at Cincinnati Children's Hospital Medical Center in 1995.

Dr. Yutzey is the first recipient of the Fifth Third Bank/Charlotte R. Schmidlapp Women Scholars Award and was also a recipient of a Children's Hospital Medical Center Trustee Award. Her work is also supported by grants from National Institutes of Health (NIH) and the American Heart Association

The focus of Dr. Yutzey's research program is the regulation of normal and abnormal heart development. Congenital heart defects represent one of the most common classes of human birth defects. Increasing evidence exists for a genetic basis of certain instances of congenital heart disease

The identification of genes responsible for these defects is an active area of research. Of equal importance are developmental studies identifying and characterizing how congenital heart defects arise during embryogenesis. These studies are dependent on the creation of well-characterized animal model systems that recapitulate human cardiovascular disease. One of the aims of the research program is to create transgenic mouse models of human congenital heart defects

The goal is to define the progression of these defects and to identify the origins of common cardiac malformations in developing embryos. The strategy is to manipulate critical regulators of heart development in specific regions of the heart at specific times during development in transgenic mice. Towards this end, several different DNA sequences that activate gene expression in different regions of the heart during development have been generated within the Division of Molecular Cardiovascular Biology

Recently, regulatory sequences that target alterations in gene expression to the precardiac region of the embryo before the heart has formed were identified. Additional DNA sequences are available that drive gene expression in the entire primitive heart or specifically in the atria or ventricles during development. With these reagents, it is now possible link temporally and spatially regulated genetic alterations in the developing heart with specific types of congenital heart disease

Recent efforts have been directed towards identifying regulators of early heart chamber development. Defects in heart chamber development represent the largest classes of human congenital cardiac anomalies. One of the few genes currently known to be associated with these defects is the transcription factor TBX5. Mutations in TBX5 have been identified in families with Holt-Oram Syndrome which includes atrial septal defects and other cardiac anomalies. Based on its expression pattern during heart development, Tbx5 is a strong candidate for one of the important regulators of heart chamber formation

An area of focus in the lab is the examination of Tbx5 function during normal heart development in chicken and mouse embryos. In addition, transgenic mice are being generated with altered Tbx5 expression and function in the developing heart

Holt-Oram Syndrome is associated with specific TBX5 mutations that likely produce proteins with altered regulatory functions. Studies are in progress in which mutant Tbx5 proteins are being expressed in the hearts of transgenic mice. The anticipated result that these mice will be born with congenital heart defects. These mice will then be used for examining the origins and progression of congenital heart lesions observed in the human population

Additional efforts in the lab are focused on the regulation of the earliest stages of normal heart development. Specifically, the molecular signals that specify some cells but not others as heart cells during embryonic development are being examined. These studies have potential applications to the treatment of degenerative cardiac disease. At present there is no reliable method for regenerating diseased cardiac cells or for driving multipotential cells such as embryonic stem cells into the cardiac lineage

The identification of specific molecular pathways involved in early cardiac development will provide potential targets for drug discovery and gene therapy. Mouse and chicken embryo culture systems are used in to examine the regulatory pathways that control early heart development. Through these studies, specific tissue interactions and molecular signals required for cardiac development have been identified. Combinations of signals that increase the numbers of cardiac cells will then be tested on multipotential stem cell populations. In the long term, these studies may be extremely valuable in efforts to generate increased numbers of cardiac cells for tissue engineering or a variety of therapeutic applications.

Credentials

BA Oberlin College, Oberlin, Ohio, 1986
PhD: Purdue University, West Lafayette, Ind., 1992
Fellowship: Cornell University Medical College, New York, Ny., 1992-1995

Position History

1992 - 1995 Post-doctoral Research Associate, Cornell University Medical College, New York, NY. Mentor: David Bader

1995 - 2002 Assistant Professor, Pediatrics-Affiliated, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center

2002 - 2007 Associate Professor, Pediatrics-Affiliated, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center

2007 - Present Professor, Pediatrics-Affiliated, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center

2004 - 2009 Director, Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center

Awards and Honors

1996-1998 Trustee Grant Award, Children's Hospital Research Foundation
1998-1999 Fifth Third Bank/Charlotte R. Schmidlapp Award
2001-2004 Established Investigator, American Heart Association
2002-2003 Co-Chair, Basic Cell and Molecular Biology-2 Peer Review Committee: American Heart Association-National
2002 Ad Hoc Peer Review: Cardiovascular B Special Emphasis Panel NIH
2002 Member Tissue Engineering Special Emphasis Panel NIH/NHLBI
2002-present Developmental Dynamics Editorial Board
2003 Program Project Grant Special Emphasis Panels (2) NIH/NHLBI
2003 Ad Hoc Peer Review: Cell Development and Function 5 (CDF-5) NIH
2003-present AHA Basic Research Council, Ohio/Virginia/Florida Affiliate
2004 Chair, American Heart Association, Basic-2 Peer Review Committee
2004-2005 Ad Hoc Peer Review: Cardiovascular Diff'n and Development (CDD) NIH
2005 AHA-National Science Classification Task Force
2005-present Stem Cells, Editorial Board
2005-present Weinstein Conference on Cardiovascular Development, Organizing Committee
2006-2010 Member, Program Project Review Parent Committee NIH/NHLBI
2007-present Developmental Biology, Editorial Board
2008-present Fellow of the Graduate School, University of Cincinnati
2009 Richard Akeson Excellence in Graduate Teaching Award, University of Cincinnati
2009-pres Fellow of the American Heart Association

Research

The focus of our studies is the molecular regulation of embryonic heart development. Experimental embryological, genetic and molecular approaches are used for mechanistic analyses of early cardiac lineage determination and heart morphogenesis. We use both chick and mouse embryonic systems to identify critical regulatory interactions responsible for these events and to manipulate these interactions in vivo. In addition, several in vitro culture systems have been developed in which to examine the molecular regulatory events that control cardiac lineage determination and early heart chamber morphogenesis. Together these strategies are employed to establish the relationships between signaling pathways and transcription factors that control the specification of the cardiomyogenic lineage and heart chamber formation. These studies have potential clinical implications in efforts to convert multipotential stem cells to the cardiac lineage and in the diagnosis and treatment of congenital heart disease.

Recent efforts in the lab have been directed towards identifying regulators of early heart lineage determination. These studies are designed to identify the molecular signals that specify some cells but not others as heart cells during embryonic development. One of the first genes expressed in the embryonic heart is the homeobox transcription factor nkx-2.5. We have identified early cardiac regulatory sequences of the nkx-2.5 gene and are studying the molecular regulatory interactions required for gene activation in the developing heart. Through these studies, specific tissue interactions and molecular signals required for cardiac development have been identified. In the long term, these studies may be extremely valuable in efforts to generate increased numbers of cardiac cells for tissue engineering or a variety of therapeutic applications.

An additional focus of the lab is the study of heart chamber formation. Defects in heart chamber development represent the largest classes of human congenital cardiac anomalies. An example of a developmentally regulated gene associated with these defects is the transcription factor TBX5. Based on its expression pattern during heart development, Tbx5 is a strong candidate for one of the important regulators of heart chamber formation. We are examining Tbx5 function during heart development in chicken and mouse embryos. A long term goal of these studies is the generation of transgenic mice born with congenital heart defects. These mice will then provide a unique tool for the examination of the origins and progression of congenital heart lesions observed in the human population.

Research Grants and Contracts

Current Support

NIH R01 HL082716 Tbx20 regulation of heart valve development. K. Yutzey, P.I. (25% effort). Total direct costs $1,000,000. 2006-2010

NIH R01 HL094319 Notch signaling in heart valve development and disease K. Yutzey, P.I. Total direct costs $607,000. 2009-2011

NIH P01 HL069779-06 The Akt/FoxO pathway in heart development. K. Yutzey, component P.I. (25% effort); J. Robbins, PPG P.I. Total component direct costs $1,053,839. 2002-2012

NIH R01 HL082716 Twist1 regulation of valve progenitors. K. Yutzey. Total direct costs $1,250,000. 2010-2015

Trainee Support

American Heart Association-Great Rivers Affiliate, Post-doctoral Fellowship #0825627D Twist1 and Tbx20 function in heart valve development. Santanu Chakraborty, Fellow. K. Yutzey, Sponsor. Total direct costs $88,000. 2008-2010

American Heart Association-Great Rivers Affiliate, Pre-doctoral Fellowship The function of Notch1 in heart valve development. Tim Mead, Fellow. K. Yutzey, Sponsor. Total direct costs $42,000. 2009-2011

American Heart Association-Great Rivers Affiliate, Pre-doctoral Fellowship Tbx18 regulation of epicardial-derived cell proliferation, migration and differentiation in cardiac development Caitlin Braitsch, Fellow. K. Yutzey, Sponsor. Total direct costs $42,000. 2009-2011

Publications, Most Recent

DiGeorge syndrome, Tbx1, and retinoic acid signaling come full circle. Yutzey, KE. Circ. Res. Invited editorial 2010 (In press).

T-box factors. Heart Development and Regeneration. Conlon, F and KE Yutzey. Academic Press. N. Rosenthal and R. Harvey ed. 2010 (In press).

Wnt signaling in heart valve development and osteogenic gene induction. Alfieri CM, Cheek J, Chakraborty S, Yutzey KE. Dev Biol. 2010 Feb 15;338(2):127-35.

Transcriptional Regulation of Heart Valve Progenitor Cells. Chakraborty S, Combs MD, Yutzey KE. Pediatr Cardiol. 2009 Dec 29.

FoxO transcription factors promote autophagy in cardiomyocytes. Sengupta A, Molkentin JD, Yutzey KE. J Biol Chem. 2009 Oct 9;284(41):28319-31.

VEGF and RANKL regulation of NFATc1 in heart valve development. Combs MD, Yutzey KE. Circ Res. 2009 Sep 11;105(6):565-74.

Heart valve development: regulatory networks in development and disease. Combs MD, Yutzey KE. Circ Res. 2009 Aug 28;105(5):408-21.

Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development. Mead TJ, Yutzey KE. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14420-5.

Notch1 regulates the fate of cardiac progenitor cells. Boni A, Urbanek K, Nascimbene A, Hosoda T, Zheng H, Delucchi F, Amano K, Gonzalez A, Vitale S, Ojaimi C, Rizzi R, Bolli R, Yutzey KE, Rota M, Kajstura J, Anversa P, Leri A. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15529-34.

Shared gene expression profiles in developing heart valves and osteoblast progenitor cells. Chakraborty S, Cheek J, Sakthivel B, Aronow BJ, Yutzey KE. Physiol Genomics. 2008 Sep 17;35(1):75-85.

Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult. Hinton RB Jr, Alfieri CM, Witt SA, Glascock BJ, Khoury PR, Benson DW, Yutzey KE. Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2480-8.

Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development. Shelton EL, Yutzey KE. Dev Biol. 2008 May 1;317(1):282-95.

Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors. Evans-Anderson HJ, Alfieri CM, Yutzey KE. Circ Res. 2008 Mar 28;102(6):686-94

Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. Lincoln J, Kist R, Scherer G, Yutzey KE. Dev Biol. 2007 May 1;305(1):120-32.

Principles of genetic murine models for cardiac disease. Yutzey KE, Robbins J. Circulation. 2007 Feb 13;115(6):792-9.

Developmental regulation of the mouse IGF-I exon 1 promoter region by calcineurin activation of NFAT in skeletal muscle. Alfieri CM, Evans-Anderson HJ, Yutzey KE. Am J Physiol Cell Physiol. 2007 May;292(5):C1887-94.

Tbx20 regulation of endocardial cushion cell proliferation and extracellular matrix gene expression. Shelton EL, Yutzey KE. Dev Biol. 2007 Feb 15;302(2):376-88.