MECHANISMS AND THERAPY OF CIRCULATORY DISEASE

  • Field, Loren (PI)
  • Jones, Larry (PI)
  • Watanabe, August (PI)
  • Besch, Henry (PI)
  • Knoebel, Suzanne (PI)
  • Bailey, John (PI)
  • Prystowsky, Eric (PI)
  • Gilmour, Robert (PI)
  • Zipes, Douglas (PI)
  • Fisch, Charles (PI)
  • Hathaway, David (PI)
  • De Paoli- Roach, Anna (PI)
  • De Paoli- Roach, Anna A. (PI)

Project: Research project

Description

The overall goal of this program project is to generate new knowledge
concerning specific molecular mechanisms that modulate the major
functions of cardiac and vascular muscle, including contractility, growth
and cellular proliferation. The unifying subtheme selected for this
competitive renewal is: Ca2+ and protein phosphorylation: interacting
subcellular mechanisms that modulate contractile and growth properties
of cardiac and vascular muscles. This group of investigators will
pursue, through interactive and collaborative studies, four major
objectives under the general subtheme: 1) To evaluate the role of
selected cell cycle regulatory proteins in the induction or maintenance
of cardiac cellular proliferation by targeted expression in transgenic
animal models; 2) To delineate the mode of regulation of key protein
phosphatases implicated in modulation of growth, cell cycling and
contractile function of cardiac and vascular cells; 3) To determine the
role of Ca2+ in cardiac muscle contraction and cellular proliferation via
specific investigation of intracellular uptake and release mechanisms;
and 4) To identify and characterize specific steps in the vascular cell
cycle that are dependent upon irreversible protein modification via
Ca2+-dependent proteolysis. Four projects and three core units have been
assembled to address these objectives. Project 1 investigates
Ca2+-dependent cysteine proteases in regulation of the vascular cell
cycle. Project 2 explores the mechanisms of cardiomyocyte proliferation
by expressing mutant growth regulatory proteins in transgenic mice.
Project 3 analyzes Ca2+ transport mechanisms in cardiac sarcoplasmic
reticulum via structural/functional analysis of the proteins,
phospholamban and Ca 2+ ATPase. Project 4 studies the regulation of
phosphoprotein phosphatases common to both cardiac and vascular tissues
that modulate contractility and growth. Collectively, this Program
Project applies the methodologies of protein biochemistry and molecular
biology to investigate highly fundamental mechanisms of cellular
regulation in cardiovascular tissues. The common use of transgenic
animal models to explore protein function in a physiological milieu
promises to yield novel observations at several levels including both
growth and contractile function. The basic studies proposed have
important implications to the health-related problems of heart failure,
regeneration of cardiac muscle and modulation of vascular tissue growth.
StatusFinished
Effective start/end date3/1/785/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,222,871.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $1,492,445.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Blood Vessels
Myocardium
Growth
Proteins
Cell Proliferation
Cardiac Myocytes
Transgenic Mice
Genetically Modified Animals
Calpain
Cell Cycle Proteins
Cysteine Proteases
Cardiovascular System
Cell Cycle
Muscle Contraction
Molecular Biology
Biochemistry
Proteolysis
Phosphoric Monoester Hydrolases
Adenosine Triphosphatases
Regeneration

ASJC

  • Medicine(all)