Model Organisms in Drug Discovery

262 SATURATION SCREENING OF DRUGGABLE MAMMALIAN GENOME
been developed with the capacity to provide quantitative and imaging data on
the three-dimensional structure of mouse bones. This technique has been used
to demonstrate the efficacy of parathyroid hormone in a mouse model of
osteoporosis (Alexander et al., 2001) and to describe in three dimensions the
changes in bone resulting from the osteopetrotic mutation, which leads to
osteopetrosis (Abe et al., 2000). We use a Scanco Medical mCT40 machine for
measurements of bone mineral density. This machine permits visualization of
trabecular bone structure, which is critical in evaluating overall bone quality.
This is a much more sensitive analysis of bone than can be achieved using
DEXA alone and is a specialized test for osteoporosis that we have
implemented as part of our Level 1 analysis.
Level 2 osteoporosis tests
In Level 2, targets are analyzed to determine whether changes in bone mineral
density are due to effects on bone deposition or bone resorption using the
following tests:
. DEXA
. Micro-CT
. Undecalcified bone histomorphometry
. Bone histopathology
. Measurement of urinary helical peptide
Cardiology
The major disease areas of interest in cardiology are hypertension,
thrombosis, atherosclerosis and heart failure.
Level 1 tests
Blood pressure
Blood pressure measurements allow us to find targets that, upon inhibition,
lead to a reduction in blood pressure. Angiotensin-converting enzyme
inhibitors and angiotensin receptor antagonists are very successful drugs in
the treatment of hypertension. Both knock-outs have low blood pressure.
Blood pressure is measured using a non-invasive computerized tail-cuff
system, the Visitech Systems BP-2000. First described by Krege et al. (1995),
this technique has been validated by several studies (Ito et al., 1995; Oliver