Progress 09/15/01 to 09/14/04
Outputs
Epigenetic changes (i.e., self-perpetuating gene regulatory systems that are not dependent solely on DNA sequence, through, for example, methylation) are likely among the mechanisms underlying links among diet-health-genetic endowments. Thus, significant effort has targeted the study of epigenetic regulatory mechanisms in the last year. One project identified a DNA sequence that regulates the establishment of DNA methylation. This work is relevant to risks to chronic diseases such as diabetes. A key nutrient in the regulation of methylation is folate. Thus, significant effort has targeted mechanisms that link impaired folate-dependent one-carbon metabolism and risk for disease. This work resulted in the identification of a new pathway for the regulation of folate accumulation and the regulation of cellular methylation reactions. These motivated the development of a number of experimental model systems designed to quantify the effects of altered folate metabolism on
genome expression, genome integrity, and pathology. Associated studies have found that alterations in either intracellular folate concentrations or the expression of enzymes that generate methyl groups alter expression of about 1,000-2,000 genes, and that many of those genes are transcriptionally regulated by DNA methylation. Efforts are underway to create a custom, methylation chip, as a tool for more specific assessments of folate's role in health and disease. A complementary project is exploring folates role in the pathogenesis of cardiovascular disease and cancer buy examining how human genetic variation in folate metabolism protects against or exacerbates risks to various disease states. Disease states related to folate metabolism also are influenced by overweight and obesity and by the bodys oxidative state. Other work has succeeded in identifying key regulatory pathways for the differentiation of adipocytes, the cells that makeup body fat and examined key elements involved in
regulating the bodys oxidative state. This is a key determinant of aging and therefore to the susceptibility to chronic disease. This latter project has isolated genetic material necessary to the development of a transgenic mouse model for studies of the role of a key amino acid related to oxidative regulation, cysteine, and, presumably the determination of longevity.
Impacts
The importance of interactions among genes and environmental/ lifestyle factors is well established. Those interactions relate to health maintenance and chronic disease susceptibility (e.g. cancer and cardiovascular disease). Yet, basic mechanisms that account for the importance of those interactions are not understood. Increasing evidence that functional physiological capacity and various disease risks are affected by nutrition and that these influences may persist over multiple generations make redressing this gap particularly relevant to USDA because of the importance of food to health and USDAs roles in shaping the US food supply and in developing diet related recommendations to the public
Publications
- Verges, M., Bensadoun, A., Herz, J., Belcher, J., and Havel, R.J. 2004. Endocytosis of hepatic lipase and lipoprotein lipase into rat hepatocytes in vivo is mediated by the low density lipoprotein receptor-related protein. J. Biol. Chem. 279: 9030-9036.
- Espirito Santo, S.M.S., Pires, N.M.M., Gerritsen, G., Bovenschen, N., van Dijk, K.W., Princen, H.M.G., Bensadoun, A., Herz, J., Havekes, L.M., and van Vlijmen, B.J.M. 2004. Hepatic Low-Density Lipoprotein Receptor-Related Protein Deficiency in Mice Increases Atherosclerosis Independent of Plasma Cholesterol. Blood. 103: 3777-3782..
- Augustus, A.S., Yagyu, H., Haemmerle, G., Bensadoun, A., Vikramadithyan, R.K. Park, S.Y., Kim,J.K., Zekner, R., Goldberg, I.J. 2004. Cardiac-specific knockout of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression. J Biol Chem. 279: 25050-25057,
- Li, H., Melford, K., Judson, A., and A. Bensadoun. 2004. Murine glypican-4 gene structure and expression. Sp1 and Sp3 play a major role in glypican-4 expression in 3T3-F442A cells. Bioch. Biophys. Acta. 1679: 141-155.
- Ruel, I.L., Couture, P., Cohn, J.S., Bensadoun, A., Marcil, M., and B. Lamarche. 2004. Evidence that hepatic lipase deficiency in humans is not associated with proatherogenic changes in HDL composition and metabolism. J.Lipid Res. 45: 1528-1537.
- Stipanuk, M.H. 2004. Sulfur Amino Acid Metabolism -- Pathways for Production and Removal of Homocysteine and Cystine. Annu. Rev. Nutr. 24:539-577.
- Stipanuk, M.H. 2004. Homocysteine, Cysteine and Taurine. Modern Nutrition in Health and Disease, 10th edition, in press.
- Dominy, J. E., Stipanuk, M. H. 2004. New roles for cysteine and transsulfuration enzymes: production of H2S, a neuromodulator and smooth muscle relaxant. Nutr. Rev. 62:348-353.
- Lee, J.-I., Londono, M. P., Hirschberger, L. L., and Stipanuk, M. H. 2004. Regulation of cysteine dioxygenase and g-glutamylcysteine synthetase is associated with hepatic cysteine level. J Nutr Biochem 15: 112-122.
- Stipanuk, M. H., Hirschberger, L. L., Londono, M. P., Cresenzi, C. L., and Yu, A. F. 2004. The ubiquitin-proteasome system is responsible for cysteine-responsive regulation of cysteine dioxygenase concentration in liver. Am J Physiol Endocrinol Metab 286: E439-E448.
- Herman, H., M. Lu, M. Anggraini, A. Sikora, Y. Chang, B.J. Yoon, and P.D. Soloway. 2004. Trans allele methylation and paramutation-like effects in mice. Nat Genet 34 (2): 199-202.
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Progress 01/01/03 to 12/31/03
Outputs
Epigenetic changes (i.e., self-perpetuating gene regulatory systems that are not dependent solely on DNA sequence, through, for example, methylation) are likely among the mechanisms underlying links among diet-health-genetic endowments. Thus, significant effort has targeted the study of epigenetic regulatory mechanisms in the last year. One project identified a DNA sequence that regulates the establishment of DNA methylation. This work is relevant to risks to chronic diseases such as diabetes. A key nutrient in the regulation of methylation is folate. Thus, significant effort has targeted mechanisms that link impaired folate-dependent one-carbon metabolism and risk for disease. This work resulted in the identification of a new pathway for the regulation of folate accumulation and the regulation of cellular methylation reactions. These motivated the development of a number of experimental model systems designed to quantify the effects of altered folate metabolism on
genome expression, genome integrity, and pathology. Associated studies have found that alterations in either intracellular folate concentrations or the expression of enzymes that generate methyl groups alter expression of about 1,000-2,000 genes, and that many of those genes are transcriptionally regulated by DNA methylation. Efforts are underway to create a custom, methylation chip, as a tool for more specific assessments of folate's role in health and disease. A complementary project is exploring folates role in the pathogenesis of cardiovascular disease and cancer buy examining how human genetic variation in folate metabolism protects against or exacerbates risks to various disease states. Disease states related to folate metabolism also are influenced by overweight and obesity and by the bodys oxidative state. Other work has succeeded in identifying key regulatory pathways for the differentiation of adipocytes, the cells that makeup body fat and examined key elements involved in
regulating the bodys oxidative state. This is a key determinant of aging and therefore to the susceptibility to chronic disease. This latter project has isolated genetic material necessary to the development of a transgenic mouse model for studies of the role of a key amino acid related to oxidative regulation, cysteine, and, presumably the determination of longevity.
Impacts
The importance of interactions among genes and environmental/ lifestyle factors is well established. Those interactions relate to health maintenance and chronic disease susceptibility (e.g. cancer and cardiovascular disease). Yet, basic mechanisms that account for the importance of those interactions are not understood. Increasing evidence that functional physiological capacity and various disease risks are affected by nutrition and that these influences may persist over multiple generations make redressing this gap particularly relevant to USDA because of the importance of food to health and USDAs roles in shaping the US food supply and in developing diet related recommendations to the public
Publications
- Stipanuk, M. H. 2003. Role of the liver in regulation of body cysteine and taurine levels. Neurochem Res: 29: 105-110. Lee, J.-I., Londono, M. P., Hirschberger, L. L., and Stipanuk, M. H. (2004) Regulation of cysteine dioxygenase and g-glutamylcysteine synthetase is associated with hepatic cysteine level. J Nutr Biochem: in press.
- Stipanuk, M. H., Hirschberger, L. L., Londono, M. P., Cresenzi, C. L., and Yu, A. F. 2004. The ubiquitin-proteasome system is responsible for cysteine-responsive regulation of cysteine dioxygenase concentration in liver. Am J Physiol: in press, published online in 2003.
- Yagyu, H., Chen,G., Yokoyama, M., Hirata, K., Augustus, A., Kako, Y., Seo T., Hu, Y., Lutz,P., Merkel,M., Bensadoun, A., Homma, S. and Goldberg, I.J. 2003. Lipoprotein lipase (LPL) on the surface of cardiomyocytes increased lipid uptake and produced a cardiomyopathy. J. Clin. Inv. 111:419-426.
- Verges, M., Bensadoun, A., Herz, J., Belcher, J., and Havel, R.J. 2004. Endocytosis of hepatic lipase and lipoprotein lipase into rat hepatocytes in vivo is mediated by the low density lipoprotein receptor-related protein. J. Biol. Chem. In press, E.Pub at present.
- Lutz, E.P., Kako, Y.,Yagyu, H., Heeren, J.,Marks, S., Wright,T., Melford, K., Ben-Zeev, O., Radner,H., Merkel, M., Bensadoun, A., Wong, H., Goldberg, I.J. 2004. Mice expressing only covalent dimeric heparin-binding deficient lipoprotein lipase: Muscles inefficiently secrete dimeric enzyme. J.Biol.Chem. 279:238-244.
- Espirito Santo, S.M.S., Pires, N.M.M., Gerritsen, G., Bovenschen, N., van Dijk, K.W., Princen, H.M.G., Bensadoun, A., Herz, J., Havekes, L.M., and van Vlijmen, B.J.M. 2004. Hepatic Low-Density Lipoprotein Receptor-Related Protein Deficiency in Mice Increases Atherosclerosis Independent of Plasma Cholesterol. Blood. In press.
- Stipanuk, M. H. Londono, M., Hirschberger, L. L., Wang, L.,and Hickey, C. 2004. Evidence for expression of a single distinct form of mammalian cysteine dioxygenase. Amino Acids: in press, published online in 2003.
- Cresenzi, C. L., Lee, J.-I., and Stipanuk, M. H. 2003. Cysteine is the metabolic signal responsible for dietary regulation of cysteine dioxygenase and glutamate cysteine ligase in vivo. J Nutr 133:2697-2702.
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Progress 01/01/02 to 12/31/02
Outputs
This proposal seeks to establish a human nutritional genomics program at Cornell University that will support ongoing research projects that study research problems that have both a nutrition and genetics component. During the last 12 months, the mammalian and nutritional genomics core facilities have been established and at least 10 new transgenic mouse strains have been developed that will serve as metabolic animal models for human disease. Dr. U. Per Flodby from the Karolinska Institute, Sweden, has been hired effective February 1, 2002. Dr. Flodby has been responsible for the operation of the embryonic stem cell and genotyping core. This facility is supporting research programs that are focused on understanding the regulation of folate-dependent genes and their role in DNA stability and cancer, the role of maternal nutrition in programming fetal gene expression, and the role of proteoglycans in lipoprotein-mediated endocytosis as described in the proposal. Two
graduate student assistantships in nutritional genomics have been funded. One of these students uses mouse genetic models in their research, the second student is studying the relationships between diet and human gene variants in cardiovascular disease. Funds have also been used to support 5 seminar speakers in a series that focuses on research and discovery at the nutrition-genetics interface.
Impacts
The etiology of most nutrition-related chronic disease is comprised of interactive nutritional and heritable components. Achieving effective cross-disciplinary integration of new knowledge and research methodology with nutritional sciences is essential for all research that seeks to develop effective strategies for the management and prevention of the most common nutrition-related human diseases, including cancer and obesity, as well as chronic diseases including diabetes and cardiovascular disease. The establishment of the nutritional genomics program at Cornell will uniquely position Cornell University to be the leader in address some of the most pressing unmet public health needs.
Publications
- Stover, P. J. and Garza, C. 2002. Bringing Individuality to Public Health Recommendations. J. Nutr. 132, 2476S-2480S
- Stover, P. J. and Garza, C. 2002. Molecular and genetic considerations for long-term nutrition interventions. Asia Pacific J. Clin. Nutr. 11(S6): s129-S136.
- Garza, C and Stover, P. 2002. The role of science in identifying common ground in the GMO debate. From: IEH workshop on Gentically Modified Foods for Human Health and Nutrition.
- Haas, J.D. 2001. Biomedical research in the Division of Nutritional Sciences probes links between maternal and child nutrition and lifelong health. Connecting With Cornell. 15:10-14.
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Progress 01/01/01 to 12/31/01
Outputs
This proposal seeks to establish a human nutritional genomics program at Cornell University that will support ongoing research projects that study research problems that have both a nutrition and genetics component. During the first 12 months, funds have been designated to establish mammalian and nutritional genomics core facilities, fund graduate student assistanceships in nutritional genomics, and support a seminar series that will focus on research and discovery at the nutrition-genetics interface. Dr. U. Per Flodby from the Karolinska Institute, Sweeded, has been hired effective Feburary 1, 2002. Dr. Flodby will be responsible for the operation of the embryonic stem cell and genotyping core. Vendor quotes have been obtained for all equipment listed in the proposal, and will be purchased immediately following Dr. Flodby's approval. We anticipate that the facility will be operational by May 2002. The facility will support research programs that are focused on
understanding the regulation of folate-dependent genes and their role in DNA stability and cancer, the role of maternal nutrition in programming fetal gene expression, and the role of proteoglycans in lipoprotein-mediated endocytosis as described in the proposal. In addition, a committee has been established to select graduates students for support from this proposal. Students supported by this grant must be focused on research projects and academic training with nutrition and genetic components. Support for these students will begin in September, 2002.
Impacts
The etiology of most nutrition-related chronic disease is comprised of interactive nutritional and heritable components. Achieving effective cross-disciplinary integration of new knowledge and research methodology with nutritional sciences is essential for all research that seeks to develop effective strategies for the management and prevention of the most common nutrition-related human diseases, including cancer and obesity, as well as chronic diseases including diabetes and cardiovascular disease. The establishment of the nutritional genomics program at Cornell will uniquely position Cornell University to be the leader in address some of the most pressing unmet public health needs.
Publications
- No publications reported this period
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