Methods for identifying compounds for regulating muscle mass...

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...

Reexamination Certificate

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C435S006120, C435S007100, C435S007200, C435S069100, C435S325000

Reexamination Certificate

active

06670140

ABSTRACT:

TECHNICAL FIELD
The present invention relates to methods of identifying candidate compounds for regulating skeletal muscle mass or function or regulating the activity or expression of a corticotropin releasing factor-2 receptor (CRF
2
R). The invention also relates to methods for the treatment of skeletal muscle atrophy or methods for inducing skeletal muscle hypertrophy using CRF
2
R as the target for intervention and to methods of treating muscular dystrophies using CRF
2
R and corticotropin releasing factor-1 receptor (CRF
1
R) as targets.
BACKGROUND
CRFR and Ligands
There are two corticotropin releasing factor receptors, identified to date (CRF
1
R and CRF
2
R) which belong to G-protein coupled receptor (GPCR) class. Agonist activation of CRF
1
R or CRF
2
R 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 activation of mitogen-activated protein kinase (MAP kinase). In other studies, the enhancement of intracellular inositol triphosphate synthesis, after agonist activation of CRF receptors, suggests that CRFRs also couple to G
&agr;q
.
CRF
1
R and CRF
2
R have been cloned from human, rat, mouse, chicken, cow, catfish, frog and sheep. CRF
1
R and CRF
2
R each have a unique distribution patterns. In humans three isoforms, alpha, beta and gamma, of the CRF
2
R receptor have been cloned. Homologs for alpha and beta CRF
2
R have been identified in rat.
Several ligands/agonists of the CRFRs are known. Corticotropin releasing factor (or hormone, CRF or CRH) binds to and activates CRF
1
R and CRF
2
R. CRF is a major modulator of the body's responses to stress. This 41-amino acid peptide presides over a panoply of neuronal, endocrine, and immune processes as the primary regulator of the hypothalamus-pituitary-adrenal hormonal axis (HPA axis). In addition, there is substantial sequence homology between CRF and the amphibian peptide sauvagine as well as the telostian peptide urotensin, both of which act as agonists of CRF
1
R and CRF
2
R. These three peptides have similar biological properties as hypotensive agents and ACTH secretogogues. In addition, a mammalian congener of urotensin, urocortin, has been characterized.
The CRF receptors can be distinguished, from non-CRFRs, pharmacologically through the use of receptor selective agonists and antagonists. These selective agonists and antagonist, along with the CRFR knockout mice, have been useful in determining which CRF receptor mediates specific biological responses.
The role of CRF
1
R has been fairly well established. Mice in which the CRF
1
R gene has been ablated (CRF
1
R knockout) demonstrate an impaired stress response and reduced anxiety-like behavior. CRF
1
R is a major mediator of the HPA axis. Specifically, corticotropin releasing factor, which is released from the hypothalamus and transported to the anterior pituitary via the hypothalamic-hypophysial portal system, interacts with the CRF
1
R present on cells located in the anterior pituitary. Agonist activation of the CRF
1
R results in release of ACTH from the cells of the anterior pituitary into the systemic circulation. The released ACTH binds the ACTH receptor present on cells located in the adrenal cortex, resulting in the release of adrenal hormones including corticosteroids. Corticosteroids mediate many effects including, but not limited to, immune system suppression via a mechanism which involves thymic and splenic atrophy. Thus activation of the CRF
1
R indirectly results in the down-regulation of the immune system via activation of the HPA axis.
The role of CRF
2
R is less well developed. Mice in which the CRF
2
R gene has been ablated (CRF
2
R knockout) demonstrate an impaired food intake reduction following stimulation with urocortin, lack of vasodilation, but a normal stress response. Experiments with CRF
2
R demonstrated that CRF
2
R is responsible for the hypotensive/vasodilatory effects of CRFR agonists and for the reduction in food intake observed following treatment of mice with CRFR agonists.
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 need.
The processes by which atrophy and hypertrophy occur are conserved across mammalian species. Multiple studies have demonstrated that the same basic molecular, cellular, and physiological processes occur during atrophy in both rodents and humans. Thus, rodent models of skeletal muscle atrophy have been successfully utilized to understand and predict human atrophy responses. For example, atrophy induced by a variety of means in both rodents and humans results in similar changes in muscle anatomy, cross-sectional area, function, fiber type switching, contractile protein expression, and histology. In addition, several agents have been demonstrated to regulate skeletal muscle atrophy in both rodents and in humans. These agents include anabolic steroids, growth hormone, insulin-like growth factor I, and beta adrenergic agonists. Together, these data demonstrate that skeletal muscle atrophy results from common mechanisms in bo

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