James C. Fleet, PhD

Professor

Foods and Nutrition

Contact Information

Purdue University
700 West State St.
West Lafayette, IN 47907-2059
Phone: (765) 494-0302
Fax: (765) 494-0906
E-mail: fleet@purdue.edu

Education Background

  • B.S. in Animal Science at Cornell University in 1981
  • M.S. in Animal Nutrition at University of Delaware in 1984
  • Ph.D. in Nutritional Biochemistry at Cornell University in 1988

Awards and Honors

  • 2001 Mead-Johnson, Young Investigators Award, American Society for Nutrition Science
  • 2003 Program Committee, 12th International Workshop on Vitamin D
  • 2003 Invited Speaker, NIH Workshop on Vitamin D and Health in the 21st Century
  • 2004 University Faculty Scholar, Purdue University
  • 2005 Program Committee, 13th International Workshop on Vitamin D
  • 2007 Invited Speaker, NIH conference on Vitamin D and Cancer
  • 2009 Program Committee, 14th International Workshop on Vitamin D

Discovery

Current Funding Sources: NIH (awards from NIDDK and NCI)

Our laboratory is focused on three major themes: (1) the molecular regulation of mineral metabolism, (2) the molecular actions of vitamin D in calcium metabolism and cancer prevention, and (3) the use of genetic and genomic approaches to expand our understanding of mineral metabolism, vitamin D action, and disease prevention.

VITAMIN D OVERVIEW: Vitamin D is an essential dietary nutrient that can also be produced by skin after exposure to sunlight. Thus, low dietary vitamin D intake (a common problem in the US) and low sunlight exposure (as in the winter months) leads to low blood levels of vitamin D (low status). Experiments show that low vitamin D status is associated with higher rates of several major chronic diseases including osteoporosis and epithelial cell cancers of the breast, prostate, and colon. The work that my laboratory conducts is pertinent to these problems. We examine questions relevant to these issues using the tools of modern molecular biology in both cell and animal models.

VITAMIN D AND CALCIUM METABOLISM: Vitamin D acts in the body only after it has been metabolized to 1,25 (OH)2 vitamin D3, or calcitriol. For example, when dietary calcium intake is low, this serves as a signal to stimulate the renal conversion of 25 (OH) vitamin D3 to calcitriol. Calcitriol, in turn, stimulates the absorption of intestinal calcium absorption to compensate for the lower level of dietary calcium intake. Low efficiency of calcium absorption has recently been shown to be a risk factor for hip fracture in elderly women. In addition, the intestine of older humans and animals is resistant to the stimulatory effects of calcitriol. We are currently examining mechanisms that may account for this resistance.

VITAMIN D AND CANCER: Epithelial cell cancers result from the accumulation of gene mutations or chromosomal aberrations in cells. These changes lead to the unrestrained cellular proliferation that is the basis for tumor formation. Evidence from populations, animals, and cells suggest that high vitamin D status reduces the risk for certain cancers and that calcitriol can suppress cellular proliferation and promote the development of mature epithelial cells. Recent evidence suggests that calcitriol can be formed within the epithelial cells of the colon and prostate (i.e. renal conversion is not necessary). The molecular mechanism for the anti-cancer effects of calcitriol is not clear. Our lab conducts mechanistic and translational studies on the mechanism of calcitriol-mediated cancer prevention. Our work focuses on the prostate and colon.

GENOMIC ANALYSIS OF TRANSCRIPTION FACTOR FUNCTION: Calcitriol modulates gene transcription by interacting with the vitamin D receptor (VDR). The VDR-calcitriol complex directly interacts with DNA but the genes regulated by this interaction are not known with certainty. This question is relevant both to the molecular control of calcium metabolism and the prevention of cancer. Similarly, we are interested in the transcriptional processes that mediate the differentiation of intestinal cells into absorptive epithelial cells or mature colonocytes. We use DNA microarrays to identify transcripts whose levels change under various treatment conditions (e.g. calcitriol treatment, transfection of transcription factors into cells). In addition, we use and develop tools that permit genome-wide identification of of transcription factor binding sites (e.g. ChIP-sequencing). We believe that these global approaches are necessary to understand the complexity of biological systems relevant to the control of mineral metabolism and cancer prevention.

GENETIC CONTROLS OF MINERAL METABOLISM: Many studies, including our own, use transgenic and knockout mice to evaluate the role that specific proteins play in biological processes (i.e. a reverse genetics approach). As alternate way to learn how a physiologic system is controlled is to use a forward genetics approach whereby the genes controlling the variability in a phenotype (e.g. intestinal calcium absorption) is use to identify the genetic controls over the trait. This approach uses models with known natural genetic variation and couples the mapping of traits to genes using statistical approaches like quantitative trait loci (QTL) mapping. We are currently using this approach in various recombinant inbred lines of mice as well as in congenic and consomic mouse lines. Our goal is to find the genes controlling the metabolism of mineral elements, especially calcium. We are also interested in learning how genetics controls the response of mice to dietary mineral inadequacy.

Discovery Publications (selected)

Xu, Y. and Fleet, J.C. (2009) Complete recovery of the VDR knockout phenotype by villin-directed expression of VDR in the intestine. Gastroenterology Accepted.

Cui, M., Klopot, A., and Fleet, J.C., (2009) The impact of differentiation on 1,25 dihydroxyvitamin D-mediated gene expression in the enterocyte-like cell line, Caco-2. J. Cell Physiol. 218:113-21.

Cui, M., Zhao, Y., Hance, K.W., and Fleet, J.C. (2009) MAPK signaling enhances 1,25 dihydroxyvitamin D-mediated CYP24 gene expression in the enterocyte-like cell line, Caco-2. A differential role for Ets1 phosphorylation depending upon the state of differentiation. J. Cell Physiol. 219:132-142.

Fleet, J.C., Gliniak, C., Zhang, Z., Xue, Y., Barzan, K., McCreedy, R., and Adedokun S.A. (2008) Serum metabolite profiles and target tissue gene expression define the impact of cholecalciferol intake on calcium metabolism in rats and mice. J. Nutr. 138:1114-1120.

Rowling, M.J., Gliniak, C., Welsh, J., Fleet, J.C. (2007) High dietary vitamin D can recover the bone phenotype of CYP27B1 null mice. J. Nutr. 137:2608-2615.

Klopot, A., Hance, K.W., Peleg, S., Barsony, J. and Fleet, J.C. (2007) Nucleo-cytoplasmic Cycling of the Vitamin D Receptor in the Enterocyte-like Cell Line, Caco-2. J. Cell. Biochem. 100:617-28.

Marks, H.D., Fleet, J.C., Peleg, S. (2007) Transgenic expression of the human vitamin D receptor (hVDR) in duodenum of VDR-null mice attenuates age-dependent decline in calcium absorption. Proceedings of the 13th Workshop on Vitamin D. J. Steroid Biochem. Mol. Biol. 103:513-6.

Song, Y. and Fleet, J.C. (2007) 1,25 Dihydroxyvitamin D-Mediated Intestinal Calcium Absorption is Blunted in Mice Heterozygous for the VDR Knockout Allele. Endocrinology. 148:1396-402.

Wang, L., Klopot, A., Freund, J.N., and Fleet, J.C. (2004) HNF1-alpha and cdx-2 control calbindin D9k gene expression during cellular differentiation. Am. J. Physiol. 287:G943-953.

Ismail, A., Nguyen, CV, Ahene, A. Fleet, JC, Uskodovic, MR, and Peleg, S. (2004) Effect of cellular environment on the selective activation of the vitamin D receptor by 1alpha,25-dihydroxyvitamin D3 and its analog Ro-26-9228. Mol. Endocrinology 18:874-87.

Books, Chapters, and Monographs Publications

Fleet, J.C. (2009) Vitamin D and Cancer. In “Bioactive Compounds and Cancer” J. Milner and D. Romognolo Eds. Human Press. In Press

Fleet, J.C. (2008) Molecular Actions of Vitamin D relevant to Cancer prevention. Molecular Aspects of Medicine 29(6):388-96.

Fleet, J.C. (2007) Using genomics to understand intestinal biology. J. Physiol. Biochem. 63:83-96.

Fleet, J.C. (2007) What have genomic and proteomic approaches told us about vitamin D and cancer? Nutr. Rev. 65:S127-130.

Fleet, J.C. (2007) Renal cell cancer and nuclear receptor levels--biomarkers or functionally relevant? J. Urol. 2007 178:1144-5.

Fleet, J.C. (2006) Dairy consumption and the prevention of colon cancer: is there more to the story than calcium? Am J Clin Nutr. 83(3):527-8.

Fleet, J.C. (2006) Molecular regulation of calcium metabolism. In "Calcium in Human Health", Humana Press, C. Weaver, and R. Heaney editors, Chapter 11.

Fleet, J.C. (2004) Genomic approaches to understand vitamin D action. In "Genomics and Proteomics in Nutrition", C.D. Berdanier and N. Moustaid eds. Marcell Decker, Inc. NY, pp 237-256.

Weaver, C.M., and Fleet, J.C. (2004) Vitamin D requirements: current and future. Am. J. Clin. Nutr. 80:1735S-1739S.

Fleet, J.C. (2004) New methodologies for probing the role of vitamin D in biology. Am. J. Clin. Nutr. Supplement reporting the details of the NIH conference “Vitamin D in the 21st Century: Bone and Beyond.” 80:1730S-1734S.

Learning

Courses

Nutrition and Cancer (F&N 590C) This course examines the nature of cancer and the interaction between individual nutrients and cancer risk. The course relies on the discussion of primary literature.

Nutritional Biochemistry and Physiology I (F&N 605) - Its goal is to provide a foundation in the scientific concepts relevant to nutrient metabolism and nutrient-disease interaction. Topics covered in this semester include: cell biology of the intestine, nutrient transport, carbohydrate metabolism, and mineral metabolism.

Nutrition and Genetics (F&N 590G - special topics) - The goal of this course is to examine the general principles governing the genetic contributions to complex diseases and to review literature that indicates that diet or lifestyle factors can modify genetic susceptability to disease. The course relies on the discussion of primary literature.

Nutrition and Genomics (F&N 590 - special topic) This course examines how the information from the human genomic project is influencing our understanding of cell biology and molecular diagnostics. We focus on examples that are relevant to nutrition science by using examples from the primary literature.

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