Brain-derived membrane-associated CRF binding proteins

Details Brain-derived membrane-associated CRF binding proteins Brain-derived membrane-associated CRF binding proteins

1996-07-02

1999-06-08

Hutzell, Paula K.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

536 235, C07H 2104, C12P 2102

Patent

active

059104287

DESCRIPTION:

BRIEF SUMMARY
This invention relates generally to controlling the biological effect of Corticotropin releasing-factor (CRF) in mammals and more particularly to CRF binding proteins (CRF-BP) which are expressed on cell surfaces in the brain and have a high affinity for CRF.


BACKGROUND OF THE INVENTION

Stress is the demand placed upon an organism subjected to real or perceived threat or challenge. In order to maintain homeostasis, the organism mounts an array of hormonal, autonomic and behavioral responses, some of which are common to most stressful circumstances, such as activation of the pituitary adrenal axis and sympathetic nervous system and behavioral arousal. The stress response in large part is regulated through Corticotropin-Releasing Factor (CRF), a 41-residue hypothalamic peptide that stimulates the secretion and biosynthesis of pituitary ACTH, leading to increased adrenal glucocorticoid production. This process is regulated through a negative feedback loop whereby glucocorticoids suppress CRF production.
Although originally isolated and characterized on the basis of its role in this hypothalamopituitary-adrenal (HPA) axis, CRF has been found to be distributed broadly within the central nervous system as well as in extraneural tissues, such as the adrenal glands and testes, where it may also act as a paracrine regulator or a neurotransmitter. Moreover, the involvement of CRF in affective disorders, such as depression and anorexia nervosa, and in modulating reproduction and immune responses suggests that changes in CRF expression may have important physiological consequences. For example, perturbations in the regulatory loops comprising the HPA axis often produce chronically elevated levels of circulating glucocorticoids; such patients display the physical hallmarks of Cushing's syndrome, including truncal obesity, muscle-wasting, and reduced fertility. Most cases of Cushing's syndrome are caused by ACTH-producing tumors of the pituitary or, less frequently, nonendocrine tissue. Adrenal gland tumors or ectopic adrenal tissue account for 10-30% of occurrences of the disorder, but, in contrast to the pituitary-dependent form, plasma ACTH levels are not elevated. Several patients with Cushing's syndrome have been reported with ectopic CRF-secreting tumors, leading to the proposal that CRF can chronically drive pituitary ACTH production and, in turn, glucocorticoid release. It has been suggested that excess production of CRF may cause pituitary hyperplasia, leading to microadenoma formation and excess ACTH production. That pituitary hyperplasia accompanies some CRF-secreting tumors is consistent with this proposal.
CRF is thus a very potent stimulator of the synthesis and secretion of various peptides in the human body. The rat and human species have the same CRF molecule (r/h CRF or hCRF), which is a 41-residue peptide having the structure which is set forth in U.S. Pat. No. 4,489,163. Ovine CRF (OCRF) was first characterized, and its 41-residue structure is set forth in U.S. Pat. No. 4,415,558.
Although CRF levels in human peripheral circulation are normally low, there are often elevated levels of CRF in the maternal circulation, which levels progressively increase throughout pregnancy. It has been found that the increasing concentrations of CRF in pathological cases of pregnancy, such as pregnancy-induced hypertension and pre-term labor, are substantially and significantly elevated above those found in normal pregnancies (Campbell et al., J. Clin. Endocr. & Metab., 64:1054-1059, 1987).
It is believed that this maternal plasma CRF most likely originates from the placenta wherein it plays a paracrine role. Placenta cells have been shown to respond to CRF and to produce CRF and its mRNA. Even though CRF concentrations measured in late gestational maternal plasma are similar to levels reported in rat hypothalamic portal blood, which levels are capable of stimulating ACTH release in vitro, it does not appear that there is normally overproduction of ACTH during pregnancy. However, maternal plasma ACTH concentrations

REFERENCES:
Society for Neuroscience Abstracts, vol. 19, 1-3, Nov. 7, 1993, p. A414, "Purification, of three CFR-binding protein subtypes from sheep brain", Behan, et al., (23rd Annual Meeting of the Society for Neuroscience, Washington, D.C. Nov. 7-12, 1993).
Nature, vol. 349, Jan. 31, 1991, London GB, pp. 423-426, "Cloning and characterization of the cDNAs for human and rat corticotropin releasing factor-binding proteins", Behan et al.

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