Sialic acids (Sias) are a family of acidic sugars found on vertebrate glycoconjugates, being attached to underlying oligosaccharides (glycans) in different linkages, and modified in different ways. These linkages and modifications are molecule-specific, tissue-specific and developmentally regulated. The overall goal of this grant has been to unravel the mechanisms responsible for regulating some of these linkages and modifications, and to elucidate their biological and pathological roles. Thus, we have focused on understanding the biosynthetic mechanisms responsible for their expression, the specific intrinsic lectins that recognize them, the consequences for cellular signaling, differentiation, activation and survival, and for cellular interactions with the extracellular matrix. We are also interested in their roles in mediating cell-cell interactions and extracellular signaling during tissue organization and development, as well their recognition by specific lectins of extrinsic origin. In the past, this grant has supported studies of several such Sia modifications and linkages and the recognition of such modifications and linkages by various lectins. As our most recent interesting findings have been on the human-specific loss of the common mammalian Sia N-Glycolylneuraminic acid (Neu5Gc), we propose to focus exclusively on this issue during the next grant period. We hypothesize that this genetically determined loss has many implications, ranging from basic biochemical and cell biological effects involving uptake and incorporation into some cell types, to the presence and significance of anti-Neu5Gc antibodies, to an impact on the functions of both intrinsic and extrinsic receptors that recognize Sias. In addition to biochemical and cell biological studies, and studies of certain human samples, we will use mice with a human-like defect in Neu5Gc expression, and cell lines derived from such animals. This genetic approach increases the likelihood of definitive mechanistic conclusions to bolster the observational correlations in humans.
Specific Aims are: #1, determining the fate of exogenously-introduced Neu5Gc in Neu5Gc-deficient Human cells and mice; #2, exploring the mechanism and consequences of incorporation of Neu5Gc from dietary sources, and the accompanying anti-Neu5Gc antibody response; #3, studying the consequences of human Neu5Gc loss on the evolution and function of intrinsic Sialic acid-recognizing receptors (particularly the CD33-related Siglecs); and, #4, exploring the consequences of human Neu5Gc loss on the evolution and function of extrinsic Sialic acid recognizing receptors. The extent to which some aspects of Aims #3 and #4 and their ramifications are pursued will depend on the results of #1 and #2, and on further preliminary studies. In the long run, these studies should help elucidate the molecular and cellular basis for certain diseases that appear to be uniquely or preferentially manifested in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM032373-26
Application #
7477674
Study Section
Special Emphasis Panel (ZRG1-ICI (01))
Program Officer
Marino, Pamela
Project Start
1983-08-01
Project End
2010-06-14
Budget Start
2008-08-01
Budget End
2010-06-14
Support Year
26
Fiscal Year
2008
Total Cost
$366,235
Indirect Cost
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Meng, Caicai; Sasmal, Aniruddha; Zhang, Yan et al. (2018) Chemoenzymatic Assembly of Mammalian O-Mannose Glycans. Angew Chem Int Ed Engl 57:9003-9007
Okerblom, Jonathan; Fletes, William; Patel, Hemal H et al. (2018) Human-like Cmah inactivation in mice increases running endurance and decreases muscle fatigability: implications for human evolution. Proc Biol Sci 285:
Samraj, Annie N; Bertrand, Kimberly A; Luben, Robert et al. (2018) Polyclonal human antibodies against glycans bearing red meat-derived non-human sialic acid N-glycolylneuraminic acid are stable, reproducible, complex and vary between individuals: Total antibody levels are associated with colorectal cancer risk. PLoS One 13:e0197464
Ram, Sanjay; Gulati, Sunita; Lewis, Lisa A et al. (2018) A Novel Sialylation Site on Neisseria gonorrhoeae Lipooligosaccharide Links Heptose II Lactose Expression with Pathogenicity. Infect Immun 86:
Alisson-Silva, Frederico; Liu, Janet Z; Diaz, Sandra L et al. (2018) Human evolutionary loss of epithelial Neu5Gc expression and species-specific susceptibility to cholera. PLoS Pathog 14:e1007133
Fong, Jerry J; Tsai, Chih-Ming; Saha, Sudeshna et al. (2018) Siglec-7 engagement by GBS ?-protein suppresses pyroptotic cell death of natural killer cells. Proc Natl Acad Sci U S A 115:10410-10415
Siddiqui, Shoib S; Springer, Stevan A; Verhagen, Andrea et al. (2017) The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool. J Biol Chem 292:15312-15320
Varki, Ajit (2017) Are humans prone to autoimmunity? Implications from evolutionary changes in hominin sialic acid biology. J Autoimmun 83:134-142
Okerblom, Jonathan J; Schwarz, Flavio; Olson, Josh et al. (2017) Loss of CMAH during Human Evolution Primed the Monocyte-Macrophage Lineage toward a More Inflammatory and Phagocytic State. J Immunol 198:2366-2373
Bergfeld, Anne K; Lawrence, Roger; Diaz, Sandra L et al. (2017) N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils. Proc Natl Acad Sci U S A 114:E8155-E8164

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