Laminin is a heterotrimeric, extracellular matrix (ECM) protein that has been implicated in mediating various aspects of cell function and survival. We have recently found that laminin is highly expressed in the mouse hippocampus, and that proteolytic degradation of this protein can promote the death of neurons. In this application, we propose a systematic exploration of the expression and function of laminin in the central nervous system (CNS). Specifically, we will determine the isoform(s) of laminin that is expressed in the hippocampus, identify the proteases directly responsible for its degradation and their sites of cleavage, and establish which region of laminin interacts with neurons to promote survival. Armed with this information, we will produce conditional knockout mice that lack the specific CNS laminin isoforms only in the hippocampus. These experiments will define the molecular characteristics and functional role of a critical ECM component in the mammalian CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS038472-03
Application #
6330590
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Leblanc, Gabrielle G
Project Start
1999-04-23
Project End
2003-03-31
Budget Start
2000-07-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$342,474
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Yu, Wei-Ming; Yu, Huaxu; Chen, Zu-Lin et al. (2009) Disruption of laminin in the peripheral nervous system impedes nonmyelinating Schwann cell development and impairs nociceptive sensory function. Glia 57:850-9
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Chen, Zu-Lin; Haegeli, VĂ©ronique; Yu, Huaxu et al. (2009) Cortical deficiency of laminin gamma1 impairs the AKT/GSK-3beta signaling pathway and leads to defects in neurite outgrowth and neuronal migration. Dev Biol 327:158-68
Dhadialla, Prabhjot S; Ohiorhenuan, Ifije E; Cohen, Andrew et al. (2009) Maximum-entropy network analysis reveals a role for tumor necrosis factor in peripheral nerve development and function. Proc Natl Acad Sci U S A 106:12494-9
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Yu, Wei-Ming; Yu, Huaxu; Chen, Zu-Lin (2007) Laminins in peripheral nerve development and muscular dystrophy. Mol Neurobiol 35:288-97
Schaefer, Ulrich; Vorlova, Sandra; Machida, Takuji et al. (2007) Modulation of sympathetic activity by tissue plasminogen activator is independent of plasminogen and urokinase. J Pharmacol Exp Ther 322:265-73

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