The specific aims of this research proposal are: 1) to synthesize component peptides of the elastic fiber, i.e. the repeat peptides, actual sequences containing the repeats, multicomponent models comprised of the repeats, and composities approaching tropoelastin, and 2) to develop three dimensional structures for the peptides for the purpose of understanding the molecular structure, function and pathology of the elastic fiber, utilizing the disciplines of molecular biophysics and pathobiological chemistry. The approach is to study a series of relevant molecular systems of graded, increasing complexity and to do so in each of three states, solution, coacervate and fibrous, which constitute a set of states of graded, increasing complexity. The chemical methods to be used are those of solution and solid phase peptide synthesis. The physical and computational characterizations utilize proton and carbon-13 NMR (including solid state), nuclear Overhauser effects, relaxation studies, CD and UV spectroscopies, and X-ray diffraction in a combined effort to place conformational constrains on the molecular systems and to use conformational energy analyses for further constraints in a stepwise manner to develop descriptions of preferred conformations. These data, at the Beta-spiral and twisted filament level of development, will be combined with ultrastructural characterizations of microscopy (light, scanning and conventional with negative staining) and molecular graphics to obtain a consistent and detailed description of the filamentous structures comprising the fibrous states. The methods utilized in studying the molecular pathology of each of the relevant molecular systems are: calcium-43 NMR relaxation studies to characterize calcium binding, columns made of the fibrous states to study lipid binding, serum dialysate calcification (characterized by SEM and microanalysis), and prolyl hydroxylation as it relates to fiber formation and to degradation by elastase. The elastic fiber is a primary site for the molecular pathologies of calcification and lipid deposition, and is implicated in such disease processes as atherosclerosis, pulmonary emphysema, solar elastosis, and other complications of the connective tissue which are relevant to heart and lung diseases and to aging processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029578-08
Application #
3340704
Study Section
Biophysics and Biophysical Chemistry B Study Section (BBCB)
Project Start
1982-05-01
Project End
1992-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
School of Medicine & Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Yousif, M H M; Benter, I F; Dunn, K M J et al. (2009) Role of 20-hydroxyeicosatetraenoic acid in altering vascular reactivity in diabetes. Auton Autacoid Pharmacol 29:1-12
Gowda, D C; Luan, C H; Furner, R L et al. (1995) Synthesis and characterization of the human elastin W4 sequence. Int J Pept Protein Res 46:453-63
Urry, D W; Luan, C H; Peng, S Q (1995) Molecular biophysics of elastin structure, function and pathology. Ciba Found Symp 192:4-22;discussion 22-30
Sciortino, F; Prasad, K U; Urry, D W et al. (1993) Self-assembly of bioelastomeric structures from solutions: mean-field critical behavior and Flory-Huggins free energy of interactions. Biopolymers 33:743-52
Nicol, A; Gowda, D C; Parker, T M et al. (1993) Elastomeric polytetrapeptide matrices: hydrophobicity dependence of cell attachment from adhesive (GGIP)n to nonadhesive (GGAP)n even in serum. J Biomed Mater Res 27:801-10
Hudetz, A G; Greene, A S; Feher, G et al. (1993) Imaging system for three-dimensional mapping of cerebrocortical capillary networks in vivo. Microvasc Res 46:293-309
Elsas, F J; Gowda, D C; Urry, D W (1992) Synthetic polypeptide sleeve for strabismus surgery. J Pediatr Ophthalmol Strabismus 29:284-6
Hudetz, A G (1992) Computer simulation of erythrocyte transit in the cerebrocortical capillary network. Adv Exp Med Biol 317:659-70
Urry, D W; Gowda, D C; Parker, T M et al. (1992) Hydrophobicity scale for proteins based on inverse temperature transitions. Biopolymers 32:1243-50
Hudetz, A G; Weigle, C G; Fenoy, F J et al. (1992) Use of fluorescently labeled erythrocytes and digital cross-correlation for the measurement of flow velocity in the cerebral microcirculation. Microvasc Res 43:334-41

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