Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
2000-10-23
2004-06-15
Fredman, Jeffrey (Department: 1637)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C435S007100
Reexamination Certificate
active
06750194
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods of identifying candidate compounds for regulating skeletal muscle mass or function, regulating the activity or expression of a vasoactive intestinal peptide receptors (VPAC) or regulating expression of vasoactive intestinal peptide (VIP) or VIP analogs. The invention also relates to methods for the treatment of skeletal muscle atrophy or methods for inducing skeletal muscle hypertrophy utilizing VPAC receptors as the target for intervention.
SEQUENCE LISTING DESCRIPTION
Each of the VPAC receptor protein sequences included in the sequence listing, along with the corresponding Genbank accession number and animal species from which it is cloned, is shown in Table 1.
TABLE I
CORRESPONDING
VPAC Receptor
GENBANK
subtype
SEQ ID NO:
SPECIES
ACCESSION NOS.
VPAC
1
Receptor
1
human
L13288, U11087
VPAC
1
Receptor
2
human
X75299
VPAC
1
Receptor
3
Rattus norvegicus
M86835
VPAC
1
Receptor
4
Mus musculus
NM_011703
VPAC
1
Receptor
5
Sus scrofa
U49434
VPAC
1
Receptor
6
Rana ridibunda
AF100644
VPAC
1
Receptor
7
Porcine
I28734
VPAC
1
Receptor
8
Rattus sp
E05551
VPAC
1
Receptor
9
Carassius auratus
US6391
VPAC
2
Receptor
10
human
X95097, Y18423
VPAC
2
Receptor
11
human
L40764, L36566
VPAC
2
Receptor
12
human
U18810
VPAC
2
Receptor
13
Mus musculus
D28132
VPAC
2
Receptor
14
Rattus norvegicus
Z25885
VPAC
2
Receptor
15
Rattus norvegicus
U09631
VPAC
2
Receptor
16
Rat
A43808
BACKGROUND
VPAC and Ligands
Vasoactive intestinal peptide (VIP) and its functionally and structurally related analogs (VIP analogs), are known to have many physiological functions including smooth muscle relaxation (bronchodilation, intestinal motility), regulation of microvascular tone (vasodepression) and permeability, regulation of mucus secretion, modulation of various inmmune functions (anti-inflammation, immune cell protection), neurological effects (memory improvement, hypnogenesis, food intake, circadian rhythm control, sexual behavior), maintenance of salivary gland function, developmental growth regulation and stimulation of hormone secretion (prolactin, growth hormone, insulin). VIP and VIP analogs mediate their effects through vasoactive intestinal peptide receptors via both neuronal (as putative neurotransmitters) and neuroendocrine pathways. There are two VPAC receptors identified to date (VPAC
1
and VPAC
2
). The VPAC
1
receptor has been cloned from human, mouse (
Mus musculus
), rat (
Rattus norvegicus
and Rattus sp.), pig (
Sus scrofa
), frog (
Rana ridibunda
), goldfish (
Carassius auratus
), and turkey (
Meleagris gallopavo
). The VPAC
2
receptor has been cloned from human, mouse (
Mus musculus
), and rat (
Rattus norvegicus
).
VPAC
1
and VPAC
2
receptors are classified in the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor family based on sequence homology to other members of the PACAP family. Receptors in the PACAP family are further subdivided into two subclasses based on ligand affinity. The PACAP type I receptors have a much greater affinity for PACAP than for VIP, while the PACAP type II receptors have an approximately equal affinity for PACAP and VIP. Because VPAC
1
and VPAC
2
receptors have similar affinities for PACAP and VIP, these receptors are classified as PACAP type II receptors. Selective agonists and antagonists can differentiate VPAC
1
and VPAC
2
receptors from each other, both molecularly and pharmacologically, as well as from the PACAP type I receptors. These agonist and antagonists have been useful in matching biological activity to a particular VPAC receptor subclass.
VPAC
1
and VPAC
2
receptors both belong to the G-protein coupled receptor (GPCR) class. The specificity of coupling of VPAC
1
and VPAC
2
receptors to a particular G-protein, appears to depend upon the tissue examined. In tissues such as muscle, agonist activation of VPAC
1
or VPAC
2
receptors leads to G
&agr;s
activation of adenylate cyclase. Adenylate cyclase catalyzes the formation of cAMP which in turn has multiple effects including the activation of protein kinase A, intracellular calcium release and mitogen-activated protein kinase (MAP kinase) activation. In other studies, the enhancement of intracellular inositol triphosphate synthesis after agonist activation of VPAC receptors suggests VPAC receptor coupling to either G
&agr;i
or G
&agr;q
.
Expression of VPAC
1
and VPAC
2
receptors is tissue specific and the pattern of expression of each receptor differs. In humans, the VPAC
1
receptor has been shown to be expressed in brain, adipose, liver, and heart, while the VPAC
2
receptor has been shown to be expressed in lung, pancreas, brain, kidney, skeletal muscle, stomach, heart, and placenta. In the rat, expression of the VPAC
1
receptor has been found in the pineal gland, small intestine, liver, spleen, pancreas, lung, aorta, vas deferens and brain, while expression of the VPAC
2
receptor has been shown in the stomach, intestine, skeletal muscle, spleen, pancreas, thymus, adrenal gland, heart, lung, aorta, brain, pituitary, and olfactory bulb.
Skeletal Muscle Atrophy and Hypertrophy
Skeletal muscle is a plastic tissue which readily adapts to changes in either physiological demand for work or metabolic need. Hypertrophy refers to an increase in skeletal muscle mass while skeletal muscle atrophy refers to a decrease in skeletal muscle mass. Acute skeletal muscle atrophy is traceable to a variety of causes including, but not limited to: disuse due to surgery, bed rest, or broken bones; denervation
erve damage due to spinal cord injury, autoimmune disease, or infectious disease; glucocorticoid use for unrelated conditions; sepsis due to infection or other causes; nutrient limitation due to illness or starvation; and space travel. Skeletal muscle atrophy occurs through normal biological processes, however, in certain medical situations this normal biological process results in a debilitating level of muscle atrophy. For example, acute skeletal muscle atrophy presents a significant limitation in the rehabilitation of patients from immobilizations, including, but not limited to, those accompanying an orthopedic procedure. In such cases, the rehabilitation period required to reverse the skeletal muscle atrophy is often far longer than the period of time required to repair the original injury. Such acute disuse atrophy is a particular problem in the elderly, who may already suffer from substantial age-related deficits in muscle function and mass, because such atrophy can lead to permanent disability and premature mortality.
Skeletal muscle atrophy can also result from chronic conditions such as cancer cachexia, chronic inflammation, AIDS cachexia, chronic obstructive pulmonary disease (COPD), congestive heart failure, genetic disorders, e.g. muscular dystrophies, neurodegenerative diseases and sarcopenia (age associated muscle loss). In these chronic conditions, skeletal muscle atrophy can lead to premature loss of mobility, thereby adding to the disease related morbidity.
Little is known regarding the molecular processes which control atrophy or hypertrophy of skeletal muscle. While the initiating trigger of the skeletal muscle atrophy is different for the various atrophy initiating events, several common biochemical changes occur in the affected skeletal muscle fiber, including a decrease in protein synthesis and an increase in protein degradation and changes in both contractile and metabolic enzyme protein isozymes characteristic of a slow (highly oxidative metabolism/slow contractile protein isoforms) to fast (highly glycolytic metabolism/fast contractile protein isoforms) fiber switch. Additional changes in skeletal muscle which occur include the loss of vasculature and remodeling of the extracellular matrix. Both fast and slow twitch muscle demonstrate atrophy under the appropriate conditions, with the relative muscle loss depending on the specific atrophy stimuli or condition. Importantly, all these changes are coordinately regulated and are switched on or off depending on changes in physiological and metabolic
Isfort Robert Joseph
Sheldon Russell James
Bott Cynthia M.
Desai Naishadh N.
Fredman Jeffrey
McMahon Mary Pat
Strzelecka Teresa
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