Abstract: The present invention is directed to methods to decrease body weight and/or body fat in an animal, e.g., in the treatment of overweight or obese patients (e.g., humans or companion animals), or as a means to produce leaner meat in food stock animals (e.g., cattle, chickens, pigs), and methods to treat eating disorders (e.g., binge eating disorder and bulimia) in patients in need thereof by administering a PDE9 inhibitor. The invention also features biological tools to further study PDE9 function, i.e., genetically-modified mice and animal cells having a PDE9 gene disruption.

Abstract: The invention provides genetically-modified non-human mammals and genetically-modified animal cells containing a disrupted RAMP1, RAMP2, or RAMP3 gene. Also provided by the invention are methods of screening for agents that modulate the activity or expression of a RAMP and methods of treating mammals to modulate liver function and/or muscle metabolism.

Abstract: The invention provides transgenic, non-human animals and transgenic non-human mammalian cells harboring a transgene encoding a p25 (activator of the protein kinase cdk 5) polypeptide. The two neuropathological lesions associated with Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (NFTs), composed predominantly of amyloid &bgr; peptides and hyperphosphorylated tau, respectvely. While animal models for plaque formation exist, there is no animal model that recapitulates the formation of NFTs. This invention provides transgenic mice that overexpress human p25, an activator of cdk5, resulting in tau that is hyperphosphorylated at AD-relevant epitopes. Deposition of tau is detected in the amygdala, thalamus and cortex. Increased phosphorylated neurofilament, silver-positive neurons and neuronal death are also observed in these regions. We conclude that the overexpression of p25, an activator of cdk5, is sufficient to produce hyperphosphorylation of tau and neuronal death.

Abstract: The invention provides transgenic, non-human animals and transgenic non-human mammalian cells harboring a transgene encoding a p25 (activator of the protein kinase cdk 5) polypeptide.

Abstract: The invention features non-human mammals and animal cells that contain a targeted disruption of a kinase suppressor of Ras (KSR) gene.

Abstract: The present invention provides a genetically-modified, non-human mammal having an altered body fat composition, wherein said mammal comprises an exogenous mutant p85 PI3-K gene, wherein the expression of said gene is driven by an insulin responsive cell specific promoter. The present invention also relates to transgenic cell lines containing the same mutant gene, as well as methods using both animals and/or cells.

Abstract: The invention provides genetically-modified non-human mammals and genetically-modified animal cells containing a disrupted RAMP1, RAMP2, or RAMP3 gene. Also provided by the invention are methods of screening for agents that modulate the activity or expression of a RAMP and methods of treating mammals to modulate liver function and/or muscle metabolism.