Abstract

The objectives of the proposed studies are two-fold and reflect research areas in the biochemistry, functional properties, and cell biology of PN- 2/AbetaPP that are currently funded by two research grants. First, the biochemical interactions between PN-2/AbetaPP and coagulation factors will be investigated. Specifically, the present proposal will focus on studies concerning interactions between coagulation factor X1a and PN-2/AbetaPP and the effects of high molecular weight kininogen and the effects of biologic surfaces on these interactions. In addition, characterization of the protease inhibitory and potential anticoagulant properties of a recombinant Kunitz-type protease inhibitor domain of a related AbetaPP- homolog are planned to better understand the functional relatedness of this homolog protein to PN2/AbetaPP. Second, in a somewhat different, but related and important series of studies, PN-2/AbetaPP expression and processing in cerebral blood vessels from postmortem human brain tissue and in cultured cerebrovascular smooth muscle cells will be investigated. These series of investigations will begin to elucidate how PN-2/AbetaPP may normally serve as an anticoagulant in the cerebrovasculature and how it may abnormally be involved with intracerebral hemorrhaging in patients with a rare disorder that is related to Alzheimer's disease known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. Better understanding of the biochemistry and cerebrovascular cell biology of PN- 2/AbetaPP will provide insight into its normal function as well as the patho-biochemistry and pathophysiology of this protein in certain disease states.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL003229-04
Application #
2668617
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1995-03-15
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

Wagner, M R; Keane, D M; Melchor, J P et al. (2000) Fibrillar amyloid beta-protein binds protease nexin-2/amyloid beta-protein precursor: stimulation of its inhibition of coagulation factor XIa. Biochemistry 39:7420-7
Melchor, J P; Van Nostrand, W E (2000) Fibrillar amyloid beta-protein mediates the pathologic accumulation of its secreted precursor in human cerebrovascular smooth muscle cells. J Biol Chem 275:9782-91
Melchor, J P; McVoy, L; Van Nostrand, W E (2000) Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein. J Neurochem 74:2209-12
Davis, J; Cribbs, D H; Cotman, C W et al. (1999) Pathogenic amyloid beta-protein induces apoptosis in cultured human cerebrovascular smooth muscle cells. Amyloid 6:157-64
Van Nostrand, W E; Porter, M (1999) Plasmin cleavage of the amyloid beta-protein: alteration of secondary structure and stimulation of tissue plasminogen activator activity. Biochemistry 38:11570-6
Temann, U A; Geba, G P; Rankin, J A et al. (1998) Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med 188:1307-20
Verbeek, M M; de Waal, R M; Schipper, J J et al. (1997) Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem 68:1135-41
Davis, J; Van Nostrand, W E (1996) Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc Natl Acad Sci U S A 93:2996-3000
Davis-Salinas, J; Van Nostrand, W E (1995) Amyloid beta-protein aggregation nullifies its pathologic properties in cultured cerebrovascular smooth muscle cells. J Biol Chem 270:20887-90
Saporito-Irwin, S M; Van Nostrand, W E (1995) Coagulation factor XIa cleaves the RHDS sequence and abolishes the cell adhesive properties of the amyloid beta-protein. J Biol Chem 270:26265-9

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