Abstract

The twelve known carbonic anhydrases (CAs) and CA-related proteins (CA- RPs) play important roles in diverse physiological processes including respiration, bone resorption, renal acidification, gluconeogenesis, signal transduction, and formation of cerebrospinal fluid and gastric acid. The recently discovered CA IX and CA XII are related to oncogenesis and are over-expressed in certain cancers. The broad goal of this research is to study the functional genomics of this gene family to determine the importance of individual members to health and disease. We have five specific aims: 1. Complete studies characterizing the biochemical and molecular genetics of CA II deficiency. CA II deficiency is the basis for the human inborn error of metabolism producing osteopetrosis, renal tubular acidosis, and brain calcification, novel studies are also proposed on the CA II-deficient mouse. 2. Characterize the mouse doubly deficient for CA II and CA IV and determine what other CA in kidney compensates for CA IV deficiency. CA IV is the GPI-anchored membrane CA on surfaces of epithelial cells in kidney and gut and of capillary endothelial cells. The CA IV null mouse lacks the expected renal defect. 3. Characterize the CA VA gene knockout mouse, the newly discovered CA Vb, and candidates for CA V deficiency. CA VA is the mitochondrial CA thought to be involved in gluconeogenesis and ureagenesis. 4. Characterize CA IX and define its role in the regulation of cell proliferation and in oncogenesis. CA IX is a tumor-associated CA that is over-expressed in several cancers and expressed in normal stomach. 5. Characterize the properties and the functional genomics of CA XII. CA XII is a newly discovered, transmembrane CA that is over-expressed in several cancers and expressed in normal kidney and intestine. These studies should enhance our understanding of how thee individual carbonic anyhydrases contribute to normal physiology, how single CA deficiencies produce disease, and why the newly discovered CAs IX and XII are over-expressed in certain cancers, and should also suggest new targets for isozyme-specific CA inhibitors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040163-15
Application #
6624857
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Rasooly, Rebekah S
Project Start
1988-04-01
Project End
2004-02-29
Budget Start
2002-12-01
Budget End
2004-02-29
Support Year
15
Fiscal Year
2003
Total Cost
$445,846
Indirect Cost

  Institution

Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103

  Publications

Khan, Parvez; Idrees, Danish; Moxley, Michael A et al. (2014) Luminol-based chemiluminescent signals: clinical and non-clinical application and future uses. Appl Biochem Biotechnol 173:333-55
van Karnebeek, Clara D; Sly, William S; Ross, Colin J et al. (2014) Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet 94:453-61
Waheed, Abdul; Sly, William S (2014) Membrane associated carbonic anhydrase IV (CA IV): a personal and historical perspective. Subcell Biochem 75:157-79
Shah, Gul N; Rubbelke, Timothy S; Hendin, Joshua et al. (2013) Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism. Proc Natl Acad Sci U S A 110:7423-8
Eissenberg, Joel C; Ilvarsonn, Anne M; Sly, William S et al. (2011) Drosophila GGA model: an ultimate gateway to GGA analysis. Traffic 12:1821-38
Datta, Rupak; Shah, Gul N; Rubbelke, Timothy S et al. (2010) Progressive renal injury from transgenic expression of human carbonic anhydrase IV folding mutants is enhanced by deficiency of p58IPK. Proc Natl Acad Sci U S A 107:6448-52
Casey, Joseph R; Sly, William S; Shah, Gul N et al. (2009) Bicarbonate homeostasis in excitable tissues: role of AE3 Cl-/HCO3- exchanger and carbonic anhydrase XIV interaction. Am J Physiol Cell Physiol 297:C1091-102
Datta, Rupak; Waheed, Abdul; Bonapace, Giuseppe et al. (2009) Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV. Proc Natl Acad Sci U S A 106:3437-42
Scheibe, Renate J; Mundhenk, Karsten; Becker, Tilman et al. (2008) Carbonic anhydrases IV and IX: subcellular localization and functional role in mouse skeletal muscle. Am J Physiol Cell Physiol 294:C402-12
Grubb, Jeffrey H; Vogler, Carole; Levy, Beth et al. (2008) Chemically modified beta-glucuronidase crosses blood-brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 105:2616-21

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