Regulation of Human Presenilin-1

Project Details


DESCRIPTION (From the Applicant's Abstract): Presenilin-1 (Psi) protein is
involved in a variety of critical physiological processes including
embryogenesis, CNS development, cell death, and pathogenesis of Alzheimer's
disease (AD). Psi influences mammalian development and neuronal apoptosis by
controlling the proteolytic cleavage of Notch 1 receptor, and PS1 also causes
pathogenesis of early-onset AD (FAD) by altering the processing of b-amyloid
precursor protein (APP). Thus, PS1 gene regulation plays a crucial role to
control these events. However, we do not yet understand the precise regulatory
mechanisms controlling the transcription of the PS1 gene, and in the absence of
that information it has been difficult to target the PS1 gene locus in
designing therapies to control mammalian development and AD. The experiments
proposed in this application will elucidate the regulatory mechanisms of PS1
gene transcription. A secondary aim of this proposal tests the hypothesis that
inhibition of PS1 gene expression is mediated by p53-activation. This
experiment is important because PS1 expression is linked to (i) Notch 1
mediated cell fate decision during development, (ii) neuronal apoptosis during
aging, and (iii) pathogenesis of FAD. The proposed specific aims are to: (1)
Identify and characterize trans-acting factors interacting with the human PS1
gene fragment (-118 to +178); (2) Clone novel trans-acting factors binding to
elements (-22 to -6), (+75 to +102), (+130 to +143), and identify partner
proteins interacting with Ets factors; and (3) Elucidate the mechanism of Psi
gene regulation by Ets and p53 proteins. Roles of Ets, p53, and other
trans-acting factors in PS1 transcription will be established by antibody
supershift, Dnase I foot printing, and in vivo expression of genes encoding
these factors. Novel trans-acting factors and Ets partners will be cloned by
yeast one-hybrid and two-hybrid systems respectively. Interaction of p53 and
Ets transcription factors will be determined by pull down assay. These
experiments will provide detailed analysis of trans-acting factors that are
likely to be involved in mammalian development and also in the pathogenesis of
both early-onset and late-onset Alzheimer's disease.
Effective start/end date1/07/0130/06/02