DIET AND LIFESTYLE FACTORS REDUCING RISK FOR AGE-RELATED EYE DISEASE
K Sudha
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5R01EY016886-04 from National Eye Institute
Keywords: Accounting; Address; Adopted; Age; age related; Age related macular degeneration; Age-Years; Aging; base; Biological Availability; Blood; Blood specimen; Candidate Disease Gene; Carotenoids; Collection; cost effective; Data; Data Set; density; Development; Diet; Diet good; Dietary Factors; Disease; DNA; Eating; Elderly; Environment; Epidemiologist; Eye; Eye diseases; follow-up; Funding; Fundus; gene interaction; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; genetic risk factor; genetic variant; Genome; genome wide association study; Genotype; Geographic state; Grant; Habits; Health Expenditures; High Risk Woman; indexing; insight; Intake; International; Life Style; lifestyle factors; Low Prevalence; Lutein; macula; Measurement; Measures; modifiable risk; National Eye Institute; Nutrient; nutrition; Nutritional; Odds Ratio; Participant; Pattern; Persons; Physical activity; Physicians; Pigments; Play; Population; Postmenopause; Prevention strategy; Process; Progressive Disease; prospective; public health medicine (field); Reporting; Research; Research Priority; Retina; Retinal; Retinal Diseases; Risk; Risk Factors; Role; Sampling; Sampling Studies; Staging; Testing; Time; United States; Variant; Variation (Genetics); Vitamin D; Woman; Women`s Health; zeaxanthin
Relevance: Narrative: We recently reported evidence to support protective roles of vitamin D, the macula carotenoids lutein and zeaxanthin, healthy diet patterns and physical activity against the development of early/intermediate stages of AMD. These studies further evaluate whether being genetically susceptible for developing AMD further enhances the protective benefit of healthy diets and healthy lifestyles. The findings can be used by physicians and public health officials to inform people of healthy habits which may lower risk for developing and worsening AMD, to target people who will benefit most, and to motivate people to adopt preventive strategies. These changes could dramatically lower health care expenditures devoted to treating age-related macular degeneration which are expected to rise as the United States population ages in the coming decades
Project start date: 2005-08-01
Project end date: 2013-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01EY016886-04 (2012): $546098
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to K Sudha
E3 LIGASES AND DEUBIQUITINASES IN GPCR DOWN REGULATION
K Sudha, Assistant Professor
Duke Universitycity: Durham country: United States (us)
Grant 5R01HL080525-07 from National Heart, Lung, And Blood Institute
Abstract: G protein coupled receptors (GPCRs) constitute the largest cell-surface receptor family and at least 35% of currently prescribed drugs act on these receptor molecules. GPCR signaling is critically involved in many aspects of cardiovascular function. The magnitude and extent of GPCR signaling is determined by several governing factors including the lifetime of the receptor molecule itself. During the first period of funding, we have found that ubiquitination of the cell-surface b2 adrenergic receptor (b2AR) determines its degradation in lysosomes, thus providing an ´off switch´ for attenuating cellular responses. We have identified specific enzymatic activities involved in regulating the intracellular trafficking of agonist-activated b2ARs. Thus, the RING-domain containing E3 ubiquitin ligase Mdm2 ubiquitinates the receptor associated adaptor protein b-arrestin2 and is involved in early steps of receptor internalization while the HECT- domain containing E3 ligase Nedd4 ubiquitinates the b2AR leading to receptor degradation in the lysosomes. Recruitment of both ligases to the b2AR is agonist-dependent and occurs sequentially. We have also shown that two related deubiquitinases (DUBS), USP20 and USP33 reverse this ubiquitination and prevent receptor degradation while concomitantly promoting receptor recycling to the plasma membrane. The central hypothesis for the proposed work in this competing continuation application is "b-adrenergic signaling is intimately linked to trafficking pathways and involves dynamic regulation by distinct E3 ligases and deubiquitinases". By using aortic vascular smooth muscle cells and neonatal ventricular myocytes as cellular model systems, RNAi and knockout mice, we will define the impact of ubiquitination/deubiquitination dynamics on bAR responsiveness in the cardiovascular system. The specific aims are 1) To determine the effects of lysosomal trafficking in regulating bAR signaling, 2) To elucidate the molecular mechanisms that define the recruitment and/or activation of deubiquitinases during bAR resensitization and 3) To elucidate the mechanistic role of Mdm2 in bAR signaling in the heart. The long-term goal of this project is to understand the molecular mechanisms that integrate G protein-coupled receptor trafficking and signaling, which could play a critical role in balancing physiological responsiveness. b adrenergic receptors (b1 and b2 ARs) are expressed in the heart and are important for the contractility of heart muscles, especially during stress and exercising. b2ARs also regulate the relaxation of smooth muscle cells that line the wall of blood vessels in our body. The proposed work will elucidate how cell surface expression and function of the bARs are maintained and the knowledge gained will help the development of novel therapeutics, which could be beneficial in the treatment of heart failure and blood pressure disorders
Keywords: Adaptor Signaling Protein; Address; Adenylate Cyclase; adrenergic; Adrenergic Agents; Adrenergic Antagonists; Adrenergic beta-Antagonists; Adrenergic Receptor; Affect; Affinity; Agonist; Arrestins; Attenuated; Binding (Molecular Function); Biological Models; Blood Pressure; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; carvedilol; Catecholamines; Cell Line; Cell membrane; Cell model; Cell surface; Cell Surface Receptors; Chronic; Coupled; Coupling; Cyclic AMP; Deubiquitination; Development; Disease; Drug Prescriptions; Epinephrine; Equilibrium; Exercise; Family; functional loss; Funding; G protein coupled receptor kinase; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; GRK; Half-Life; Heart; Heart failure; Homeostasis; improved; in vivo; Knockout Mice; Knowledge; Left Ventricular Function; Ligase; Link; Lysosomes; Maintenance; Mediating; Molecular; Mus; Muscle Cells; Myocardium; Neonatal; Norepinephrine; novel; novel therapeutics; Pathway interactions; Patients; Phosphorylation; Physiological; Plasma; Play; Post-Translational Protein Processing; prevent; Process; Production; Proteins; public health relevance; receptor; Receptor Down-Regulation; receptor expression; receptor internalization; receptor recycling; Receptor Signaling; Recycling; Regulation; Relaxation; response; RNA Interference; Role; Signal Transduction; Smooth Muscle Myocytes; Staging; Stress; Testing; trafficking; ubiquitin ligase; ubiquitin-protein ligase; Ubiquitination; Ventricular; Work
Relevance: Relevance: ¿ adrenergic receptors (¿1 and ¿2 ARs) are expressed in the heart and are important for the contractility of heart muscles, especially during stress and exercising. ¿2ARs also regulate the relaxation of smooth muscle cells that line the wall of blood vessels in our body. The proposed work will elucidate how cell surface expression and function of the ¿ARs are maintained and the knowledge gained will help the development of novel therapeutics, which could be beneficial in the treatment of heart failure and blood pressure disorders
Project start date: 2005-08-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01HL080525-07 (2011): $353250