The majority of congenital defects involve anomalous development of the heart, and of these most are attributed malformation of cardiac mesenchyme (CM). CM is destined to contribute to the septation process which partitions the heart into four chamber and divides the common outflow tract into the aorta and pulmonary artery as well as forming the heart valves. A key event in the formation of CM is the migration of these cells through an extensive lattice of collagen fibrils which serve as a scaffold or substratum. The long range goals of this project are to understand the molecular mechanisms which occur between a cell and its substatum during migration. The following hypotheses are proposed: (I) BOTH CELL SURFACE ASSOCIATED HS-PG AND THE FIBRONECTIN RECEPTOR COMPLEX, INTEGRIN, ARE ESSENTIAL FOR ATTACHMENT SITE FORMATION DURING MESENCHYMAL CELL MIGRATION. (II) DURING CARDIAC EMBRYOGENESIS THERE EXISTS STRUCTURAL DIVERSITY AMONGST CS-PG WHICH REFLECTS SPECIFICITY OF THE SYNTHETIC SOURCE (i.e., myocardial vs. mesenchymal). (III) THE FUNCTIONAL SIGNIFICANCE OF CARDIAC MESENCHYME DERIVED CS-PG IS TO PREVENT STATIC CYCLES OF CELL ATTACHMENT:DETACHMENT:REATTACHMENT TO SURROUNDING COLLAGEN FIBRILS VIA SUBSTRATE MASKING By CS-PG BINDING TO COLLAGEN.
The specific aims relate to the hypotheses and are: (1) to determine whether the type(s) of attachment sites formed during mesenchymal cell migration are dependent upon either cell surface associated HS-PG and/or the fibronectin receptor complex, integrin. (2) To isolate and characterize CS-PG from myocardial and CM cell cultures (e.g., relative size comparison of intact PGs, constituent GAg chains and core proteins; sedimentation coefficients). (3) To prepare antibodies that specifically recognize myocardial vs. mesenchymal CS-PG. (4) To use these antibodies as immunohistochemical tools for a regional and temporal comparison of localization patterns on in situ heart tissue from the embryonic chick heart as well as from the trisomy 16 mouse (model for Down Syndrome), which exhibits a high incidence of CM-related congenital heart defects. (5) To determine if myocardial and CM CS-PG differ in their ability to interact with native, collagen (type I) fibrils. (6) To test the model of """"""""substrate masking"""""""" by examining the capacity of an experimentally defined ECM to modulate CM cell attachment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040563-03
Application #
3357808
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1990-12-28
Budget End
1991-11-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Funderburg, F M; Langford, J K; Hiltgen, G G (1991) Chondroitin sulfate proteoglycans: do they play a role during cardiac morphogenesis? Prog Clin Biol Res 373:227-43