MURINE MODELS OF HUMAN NEURODEGENERATIVE DISEASES

  • Buettner, Christoph (PI)
  • DAVIS, KENNETH (PI)
  • DAVIS, KENNETH (PI)
  • DAVIS, KENNETH (PI)
  • DAVIS, KENNETH (PI)
  • Elder, Gregory (PI)
  • LAZZARINI, ROBERT (PI)
  • Morrison, John (PI)
  • ROBAKIS, NIKOLAOS (PI)
  • DAVIS, KENNETH (PI)
  • MOHS, RICHARD (PI)
  • BUCHSBAUM, MONTE (PI)
  • Haroutunian, Vahram (PI)
  • AISEN, PAUL (PI)
  • PERL, DANIEL (PI)
  • Coleman, David (PI)
  • ALTSTIEL, LARRY (PI)
  • MARIN, DEBORAH (PI)
  • Butler, Robert (PI)
  • FILLIT, HOWARD (PI)
  • GABRIEL, STEVEN (PI)
  • WALLACE, WILLIAM (PI)
  • GREENWALD, BLAINE (PI)
  • Haroutunian, Vahram (PI)
  • Lazzarini, Robert A. (PI)
  • Morrison, John H. (PI)
  • Robakis, Nikolaos K. (PI)
  • Perl, Daniel P. (PI)
  • Davis, Kenneth L. (PI)
  • Mohs, Richard C. (PI)
  • Fillit, Howard M. (PI)
  • GABRIEL, STEVEN (PI)
  • Wallace, William C. (PI)
  • Greenwald, Blaine S. (PI)
  • Butler, Robert N. (PI)
  • LANDAU, EMMANUEL (PI)
  • KRIEGER, DOROTHY (PI)
  • PERRY, ROBERT (PI)
  • PERRY, ROBERT (PI)
  • Elder, Gregory (PI)
  • LAZZARINI, ROBERT (PI)
  • Morrison, John (PI)
  • ROBAKIS, NIKOLAOS (PI)
  • DAVIS, KENNETH (PI)
  • MOHS, RICHARD (PI)
  • BUCHSBAUM, MONTE STUART (PI)
  • Haroutunian, Vahram (PI)
  • AISEN, PAUL (PI)
  • PERL, DANIEL (PI)
  • Coleman, David (PI)
  • ALTSTIEL, LARRY (PI)
  • MARIN, DEBORAH (PI)
  • Butler, Robert (PI)
  • LAZZARINI, ROBERT (PI)
  • HOF, PATRICK (PI)
  • Buxbaum, Joseph (PI)
  • ROBAKIS, NIKOLAOS (PI)
  • SILVERMAN, JEREMY (PI)
  • PERL, DANIEL (PI)
  • MARIN, DEBORAH (PI)
  • MOHS, RICHARD (PI)
  • Elder, Gregory (PI)
  • Morrison, John (PI)
  • BUCHSBAUM, MONTE STUART (PI)
  • AISEN, PAUL (PI)
  • Coleman, David (PI)
  • ALTSTIEL, LARRY (PI)
  • Butler, Robert (PI)
  • Sano, Mary (PI)
  • Haroutunian, Vahram (PI)
  • PERL, DANIEL (PI)
  • HOF, PATRICK (PI)
  • Buxbaum, Joseph (PI)
  • GEORGAKOPOULOS, ANASTASIOS (PI)
  • Sano, Mary (PI)
  • HOF, PATRICK (PI)
  • Buxbaum, Joseph (PI)
  • GEORGAKOPOULOS, ANASTASIOS (PI)
  • PERL, DANIEL (PI)
  • Haroutunian, Vahram (PI)
  • LUO, XIAODONG (PI)
  • SEWELL, MARGARET (PI)
  • Gandy, Samuel (PI)
  • Sakurai, Takeshi (PI)
  • Sano, Mary (PI)
  • GROSSMAN, HILLEL (PI)
  • SEWELL, MARAGARET (PI)
  • NEUGROSCHL, JUDITH (PI)
  • SCHIMMING, CORBETT (PI)
  • YOON, YONEJUNG (PI)
  • GOATE, ALISON (PI)
  • ZHU, CAROLYN WEI (PI)
  • ROBAKIS, NIKOLAOS (PI)

Project Details

Description

The long term objectives of this program are to model aspects of human
neurodegenerative diseases in mice. Murine models of Alzheimer's pathology
would facilitate studies of lesion pathogenesis and might also be used in
testing drugs designed to reverse or delay pathology.

Recently several mutations in the amyloid precursor protein (APP) gene have
been linked to familial Alzheimer's disease (FAD) and a form of congophilic
angiopathy associated with hereditary intracerebral hemorrhage (ICH).
Utilizing homologous recombination in ES cells we will introduce the FAD
717 mutation, the Swedish FAD double mutation and the codon 693 ICH
mutation into the highly homologous mouse APP gene. Animals will be
assessed for pathological and biochemical evidence of abnormal amyloid
accumulation. Additionally since the functions of the various APP isoforms
are unknown we will create mice dither lacking a functional murine APP gene
or lacking the protease inhibitor (KPI) containing forms of mouse APP.
Both mutations should be informative concerning the normal functions of
APP.

The neurons that are vulnerable in AD receive prominent glutamatergic imput
and many of the cytoskeletal alterations seen in AD neurofibrillary tangles
can be elicited by excitatory amino acids in cultured neurons. In all
forms of excitotoxicity accumulating evidence supports a central role for
altered regulation of intracellular calcium in neuronal damage. The
ability to target selected glutamate receptor subunits (GluRs) to neurons
makes it possible to test whether altering glutamate mediated calcium
influx will alter sensitivity to excitotoxic injury. Neuronal GluR
composition will be altered by targeting three rat glutamate receptors
(GluR2, GluR6 and NMDAR1) "tagged" with a heterologous amino acid sequence
to allow differentiation of transgenic from endogenous mouse GluRs. These
subunits were chosen because they are expected to either decrease (GluR2)
or increase (GluR6 and NMDAR1) calcium influx in response to GluR
activation. The human mid-sized neurofilament gene will be used as a
targeting vector since it can direct expression to a wide variety of
neurons including the cortical pyramidal cells which are heavily effected
in AD.

Finally we will extend our previous studies of neurofilament gene
regulation by mapping tissue specific DNAse I hypersensitive sites in the
human NF(M) gene. Hypersensitive regions will be assayed for their ability
to direct neuron specific expression in transgenic mice. Ultimately we
will seek to identify the transcription factors which interact with these
regions. In addition to better delineating the tissue specific control
regions of human NF(M) these studies may allow improved design of neuron
specific targeting vectors for use in transgenic mice.
StatusFinished
Effective start/end date1/1/013/31/20

ASJC

  • Clinical Neurology
  • Public Health, Environmental and Occupational Health
  • Psychiatry and Mental health
  • Neurology
  • Psychology(all)
  • Education
  • Genetics
  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Health Informatics
  • Physiology
  • Radiology Nuclear Medicine and imaging
  • Cell Biology
  • Statistics and Probability
  • Endocrinology, Diabetes and Metabolism
  • Pathology and Forensic Medicine
  • Statistics, Probability and Uncertainty