Abstract

This proposal is focused on the physiological functions of Protein Kinase A (PKA) in the regulation of? adiposity, feeding, and energy expenditure. The holoenzyme form of PKA interacts with cAMP to release? active catalytic subunits that phosphorylate a variety of intracellular targets. This process is modulated by? scaffolding proteins (AKAPs) and the expression of various isoforms of PKA with different biochemical? properties. The goal of my laboratory is to develop mouse genetic approaches that can be used to study the? role of PKA in physiological pathways that are not easily manipulated in cell culture models. Targeted? disruption of the Rllbeta regulatory subunit gene of PKA creates mice that are lean and resistant to obesity and? display a two-fold increase in nocturnal activity. These phenotypes have recently been traced to the brain? and we propose to focus our efforts on determining the brain regions and specific cell types that are? responsible. We also propose experiments to determine the changes in kinase activity that account for? these phenotypes and the potential substrates that are involved. The application of mouse genetics to the? study of body weight regulation has identified novel hormones, neural pathways, and intracellular signaling? systems that have all proven to be applicable to humans. Our goal is to further understand the signaling? interactions in the hope that this will lead to future therapeutic treatments for obesity.? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM032875-21A1
Application #
7035178
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Jones, Warren
Project Start
1997-09-30
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
21
Fiscal Year
2006
Total Cost
$349,875
Indirect Cost

  Institution

Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Flippo, Kyle H; Gnanasekaran, Aswini; Perkins, Guy A et al. (2018) AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission. J Neurosci 38:8233-8242
Li, Lei; Li, Jing; Drum, Benjamin M et al. (2017) Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve. Cardiovasc Res 113:147-159
Riggle, Kevin M; Riehle, Kimberly J; Kenerson, Heidi L et al. (2016) Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma. Pediatr Res 80:110-8
Yang, Haihua; Yang, Linghai (2016) Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy. J Mol Endocrinol 57:R93-R108
Jones, Brian W; Deem, Jennifer; Younts, Thomas J et al. (2016) Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination. Elife 5:
Gilbert, Merle L; Yang, Linghai; Su, Thomas et al. (2015) Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype. Am J Physiol Renal Physiol 308:F627-38
Sanz, Elisenda; Quintana, Albert; Deem, Jennifer D et al. (2015) Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. J Neurosci 35:5549-56
Yang, Linghai; McKnight, G Stanley (2015) Hypothalamic PKA regulates leptin sensitivity and adiposity. Nat Commun 6:8237
Yang, Linghai; Gilbert, Merle L; Zheng, Ruimao et al. (2014) Selective expression of a dominant-negative type I? PKA regulatory subunit in striatal medium spiny neurons impairs gene expression and leads to reduced feeding and locomotor activity. J Neurosci 34:4896-904
Vulto-van Silfhout, Anneke T; Rajamanickam, Shivakumar; Jensik, Philip J et al. (2014) Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. Am J Hum Genet 94:649-61

Showing the most recent 10 out of 84 publications