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Farrance, Iain, Ph.D.
Assistant Professor
Department of Biochemistry and Molecular Biology
E-mail: ifarr001@umaryland.edu

The research in my laboratory focuses on transcriptional regulation in cardiac muscle under normal and diseased conditions. Prior to birth the heart increases in size due to cell division of the cardiac myocytes. After birth the cardiac myocytes withdraw from the cell cycle and the heart increases in size due to increase in size (and contractile protein content) of each individual myocyte. This process is called cardiac hypertrophy. Heart disease caused by a1-adrenergic agonists, chronic high blood pressure, ischemic damage also causes cardiac hypertrophy. This type of hypertrophy (sometimes termed "pathological" hypertrophy) is marked by the upregulation of genes expressed during fetal life and eventually causes a decrease in cardiac function that can lead to heart failure. Studies of gene regulation during this process is especially relevant since heart failure is a leading cause of death.

Signals that cause cardiac hypertrophy alter the expression of many genes (contractile, regulatory and calcium handling). These complex gene expression changes are illustrated by the genes encoding myosin heavy chain (MHC) and actin isoforms. ß- MHC and skeletal -actin are the predominant MHC and actin isoforms in embryonic rat heart but are replaced by -MHC and cardiac -actin after birth. In the hypertrophied heart ß- MHC and skeletal -actin are reexpressed. These fetal protein isoforms adversely affect the function of the heart and must play a yet undetermined role in heart failure.

Some of the transcription factors that regulate expression of cardiac genes have been identified. These regulatory factors include the TEF-1, MEF-2 families, serum response factor (SRF), GATA-4 and USF. While the role of individual factors in regulating the expression of gene expression has been grossly determined, how the activity of these factors is regulated to achieve the complex expression patterns seen during cardiac development and in heart disease is still not known.

I am investigating the role of one family of transcription factors, the TEF-1 family, in cardiac-specific gene expression and in cardiac hypertrophy. TEF-1 binding sites are required for the expression of many contractile protein genes in muscle and for the response of these some genes to 1-adrenergic agonists. During both of these processes, the activity of TEF-1 is modulated by: 1) interactions of TEF-1 with its different types of DNA binding sites, and 2) protein:protein interactions (TEF-1 with, itself, with other TEF-1 family members, with cofactors, with other types of transcription factors, and with the basal transcriptional machinery). These interactions are the focus of the research in my laboratory.

My laboratory uses cultured cardiac myocytes for these studies because treatment of these cells with 1-adrenergic agonists mimics the cellular hypertrophy and gene expression changes seen in the diseased heart. Using molecular biology techniques (DNA transfections, assays for DNA binding proteins, interaction cloning, and structure/function analyses by deletion and mutagenesis) and this (in vitro) system we can study the role of TEF-1 and its interactions in the regulation of cardiac contractile protein genes during disease. The information from these studies could lead to improved treatment of heart disease in patients.

Farrance, I.K.G., and Ordahl, C.P., The role of transcripiton enhancer factor-1 (TEF-1) related proteins in the formation of M-CAT binding complexes in muscle and non-muscle tissues, JBC,271:8266-8274, 1996.



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Interdisciplinary Training Program
in Muscle Biology
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University of Maryland Graduate School, Baltimore
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