Research Development Foundation

Kuo-Fen Lee

Wylie Walker Vale, Jr

Chien Li

Tracy L Bale

George W Smith

Wylie W Vale, Jr

Alon Chen

Paul E Sawchenko

Robert A Rissman

Lingyun Zhao

Douglas E Vetter

Methods for treating or preventing tauopathies and/or A&#x3b2; amyloidosis by modulating CRF receptor signaling. Accumulation of hyperphosphorlyated tau protein in the CNS may be reduced by administration of CRF-R1 selective antagonists and/or CRF-R2 selective agonists. For example, in some aspects, methods for preventing the onset of Alzheimer's disease by administration of CRF-R1 selective antagonist are provided.

Methods for treatment and prevention of tauopathies and amyloid beta amyloidosis by modulating CRF receptor signaling

In some aspects, the invention relates to methods for increasing insulin-sensitivity and/or decreasing insulin secretion in an individual by reducing or inhibiting corticotropin releasing factor 2 (CRFR2) signaling. CRFR2 antagonists may block agonism by one or more CRFR2 agonist, for example Ucn 2 or Ucn 3. Methods according to the invention may be use to treat a variety of metabolic diseases such as type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease, polycystic ovarian syndrome and obesity.

Methods of increasing insulin sensitivity or decreasing insulin secretion by administering corticotropin releasing factor receptor-2 inhibitors

The present invention provides transgenic mice deficient in corticotropin releasing factor receptor 2 (CRFR2). Mice deficient for CRFR1 exhibit decreased anxiety-like behavior and a decreased stress response. In contrast, CRFR2 null mutant mice are hypersensitive to stress and display increased anxiety-like behavior. These mice are useful for the study of anxiety, depression, and the physiology of the HPA axis. CRFR2 null mutant mice also exhibit increased angiogenesis in all tissues examined. Thus, CRFR2 antagonists may be used to stimulate angiogenesis for the treatment of various conditions. In contrast, CRFR2 agonists may be used to inhibit angiogenesis. A combination of urocortin and bFGF was observed to stimulate rapid hair growth.

Method of inhibiting angiogenesis by administration of a corticotropin releasing factor receptor 2 agonist

The present invention provides transgenic mice deficient in urocortin. Urocortin null mutant mice are hypersensitive to stress and display heightened anxiety-like behaviors in the elevated plus maze and open field tests. These mice also demonstrate physiological alterations in auditory thresholds and distortion product otoacoustic emissions. These results indicate that urocortin plays a modulatory role in anxiety-related behaviors and in contributing to the establishment of auditory thresholds. Such urocortin deficient mutant mice can provide useful models in the study of anxiety pathology and hearing physiology at the biochemical and molecular levels.

Urocortin-deficient mice and uses thereof

The present invention provides transgenic mice deficient in corticotropin releasing factor receptor 2. Corticotropin releasing factor is a critical integrator of the hypothalamic-pituitary-adrenal axis in response to stress. CRF and its related molecule urocortin bind CRF receptor 1 and CRFR2 with distinct affinities. CRFR2 mutant mice were hypersensitive to stress and displayed increased anxiety-like behavior. Mutant mice had normal basal feeding and weight gain, but exhibited decreased food intake following food deprivation. Intravenous UCN dramatically decreased the mean arterial pressure in the controls but had no effect in the mutants. A deficiency of CRFR2 results in a significant increase in urocortin mRNA in the rostral region of the Edinger Westphal and a significant increase in CRF mRNA in central nucleus of the amygdala. These results demonstrate that the CRFR2 mutant mice, opposed to CRFR1 mutant mice, have an increased sensitivity to stress and display anxiety-like behavior. These mice are useful for the study of anxiety, depression, and the physiology of the HPA axis.

Corticotropin releasing factor receptor 2 deficient mice and uses thereof

Signaling pathways dependent on members of the corticotropin releasing factor (CRF) gene family exert pleiotropic effects within both the brain and peripheral tissues. Two biochemically and pharmacologically distinct corticotropin releasing factor receptor subtypes (corticotropin releasing factor receptor-1 and corticotropin releasing factor receptor-2) have been described. To study the developmental and physiological role of the specific receptor subtypes, a strain of mice null for the corticotropin releasing factor receptor-1 gene has been generated. This genetically engineered strain of mice suggest that corticotropin releasing factor receptor-1 is obligatory both in development and function of the hypothalamic-pituitary-adrenal axis and in mediating behavioral changes associated with anxiety and locomotor activity rhythms.

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Del Mar, CA, United States of America

Kuo-Fen Lee