James Fleet


Distinguished Professor
Department of Nutrition Science (NUTR)

Contact Information

Office STON G1B
Address 700 West State St.
West Lafayette, IN 47907
Phone 765.494.0302
Fax 765.494.0906
E-Mail fleet@purdue.edu

Educational Background

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

Awards & Honors

  • University Faculty Scholar from Purdue University, 2004 - Present
  • Advisory Committee for the International Workshops on Vitamin D, 2013 - Present
  • Distinguished Professor from Purdue University, 2012 - Present
  • American Gastroenterological Assn Councelor, Nutrition and Obesity Section, 2011 - 2012
  • Member, Integrative Nutrition and Metabolic Processes Study Section (NIH), 2004 - 2009
  • Advisor, Student Interest Group, American Society for Nutrition, 2013
  • Member, Chemo and Dietary Prevention Study Section (NIH), 2012
  • Cancer Research Award from Lafayette Lions Club, 2012
  • Mead-Johnson, Young Investigators Award from American Society for Nutrition Science, 2001

Activities & Memberships

  • Member, American Association for Cancer Research, 2009 - Present
  • Member, American Gastroenterological Association, 2002 - Present
  • Member, American Association for the Advancement of Science, 1999
  • Member, American Society for Nutrition, 1992 - Present
  • Member, American Society for Bone and Mineral Research, 1991 - Present

Discovery

Funding Sources: NIH (awards from NIDDK, NCI), AICR, Showalter Trust

Our laboratory is focused on two major themes: (1) the molecular regulation and genetics of of bone and mineral metabolism, (2) mechanisms of carcinogenesis and cancer prevention. Many, but not all, of our projects revolve around the role of vitamin D in health.

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). Population based studies show that low vitamin D status is associated with higher rates of several major chronic diseases including osteoporosis and epithelial cell cancers of the prostate and colon. The work that my laboratory conducts is pertinent to these problems. We use cell and animal models to directly test the validity of these associations and we examine mechanisms by which vitamin D regulates processes relevant to these conditions using the tools of physiology, genetics, and molecular biology.

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 is 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 examine the regulation of intestinal calcium absorption by calcitriol as well as test mechanisms by which calcium crosses the intestinal barrier.

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. The molecular mechanism for the anti-cancer effects of calcitriol in cancer is not clear but may include direct protective effects on epithelial/normal tissue stem cells or indirect effects mediated through anti-inflammatory actions of vitamin D on the immune system. Our lab conducts mechanistic and translational studies on the mechanism of calcitriol-mediated cancer prevention and we focus on cancers of the prostate and colon.

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 and phosphorus. We are also interested in learning how genetics controls the response of mice to dietary mineral inadequacy.


Discovery Publications

  • Jiang, Y., Cui, M., and Fleet, J.C. (2012) Phorbol esters enhance 1α,25(OH)2D3-regulated 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) gene expression through ERK-mediated phosphorylation of specific protein 3 (SP3) in Caco-2-cells. Mol. Cell Endocrinol. 361:31-39.
  • Yin, L., Unger, E.L., Jellen, L.C., Earley, C.J., Allen, R.P., Tomaszequicz, A., Fleet, J.C., and Jones, B.C. (2012) Systems genetic analysis of multivariate response to iron deficiency in mice. Am. J. Physiol. 302:R1282-1296.
  • Cui, M. and Fleet, J.C. (2012) Villin-promoter mediated transgenic of TRPV6 increases intestinal calcium absorption in wild-type and VDR knockout mice. J. Bone Min. Res. 27:2097-2107.
  • Jiang, Y. and Fleet, J.C. (2012) Effect of phorbol 12-myristate 13-acetate activated signaling pathways on 1α,25 dihydroxyvitamin D3 (1,25(OH)2D3) regulated 25-hydroxyvitamin D3 24-hydroxylase (CYP24A1) gene expression in Caco-2 cells. J. Cell. Biochem. 113:1599-1607.
  • Kovalenko, P.L., Zhang, Z., Yu, J.G., Clinton, S.K., and Fleet, J.C. (2011) Disrupting vitamin D (VD) signaling increases androgen dependent proliferation and reduces apoptosis in mouse prostate. Cancer Prevention Research.
  • Farrow, E.G., Yu, X., Summers, L.J., Davis, S.I., Fleet, J.C., Allen, M.R., Robling, A.G., Stayrook, K.R., Jideonwon, V., Magers, M.J., Garringer, H.J., Vidal, R., Chan, R.J., Goodwin, C.B., Hui, S., Peacock, M., and White, K.E. (2011) Altered FGF23 proteolytic regulation causes late-onset hypophosphatemia during iron deficiency in an ADHR mouse model. Proc. Natl. Acad. Sci. USA. 108:E1146-1155.
  • Kovalenko, P.L., Zhang, Z., Cui, M., Clinton, S.K., and Fleet, J.C. (2010) 1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, nontransformed prostate epithelial cell line, RWPE1. BMC Genomics. 11:26.
  • Zhang, Z., Kovalenko, P., and Fleet, J.C. (2010) Constitutive Activation of the Mitogen-Activated Protein Kinase Pathway impairs vitamin D signaling in human prostate epithelial cells. J Cell Physiology. 224:433-442.
  • Xue, Y., Johnson, R., DeSmet, M., Snyder, P., and Fleet, J.C. (2010) Generation of a Transgenic Mouse for Colorectoral Cancer Research with Intestinal Cre-Expression Limited to the Large Intestine. Molecular Cancer Res. 8:1095-1104.
  • 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.
  • 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.
  • Xue, Y., and Fleet, J.C. (2009) Complete recovery of the VDR knockout phenotype by villin-directed expression of VDR in the intestine. Gastroenterology. 136:317-327.
  • Ghoreishi, M., Bach, P., Obst, J., Fleet, J.C. and Dutz, J. (2009) Expansion of antigen-specific regulatory T cells with the topical vitamin D analogue calcipotriol. J Immunology. 182:6071-6078.
  • 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.
  • 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.

Engagement

Purdue Center for Cancer Research Profile of Dr. Fleet
(www.cancerresearch.purdue.edu/fleet-video)

Vitamin D Videos: A series of 6 short videos to help consumers better understand the role of vitamin D in health. (www.enjoyfoodbeactive.org/vitamind.aspx)
What is vitamin D?
Are you getting enough vitamin D?
How much vitamin D do you need?
What factors affect the amount of vitamin D you need?
Where can I get vitamin D?
Are vitamin D supplements safe?

Engagement Publications

  • Fleet, J.C. Vitamin D Fact Sheet 2010. Purdue Extension publication.

Books, Chapters & Monograph Publications

  • Johnson, R.L. and Fleet, J.C. (2013) Animal models of colorectal cancer. Cancer Metastasis Rev. [epub ahead of print].
  • Fleet, J.C., DeSmet, M., Johnson, R., and Li, Y. (2012) Vitamin D and Cancer: A review of molecular mechanisms. Biochemical Journal. 441:61-76.
  • Fleet, J.C. and Schoch, R. (2012) Regulation of calcium and phosphorus absorption by vitamin D. In: Vitamin D, 3rd Edition. D. Feldman and J.W. Pike Ed(s). Ch.19. Pp.349-362.
  • Fleet, J.C. (2012) Systems Biology and Nutrition. In: Present Knowledge in Nutrition. J.W. Erdman, I.A. Macdonald, S. Zeisel Ed(s). Ch.1. Pp.1-13. Wiley-Blackwell, Ames, IA.
  • Fleet, J.C., Replogle, R., and Salt, D.E. (2011) Systems Genetics of Mineral Metabolism. J Nutr. 141:520-525.
  • Fleet, J.C. and Schoch, R. (2010) Regulation of calcium absorption by vitamin D and other hormones. Critical Reviews in Clinical Laboratory Sciences. 47:181-195.
  • Fleet, J.C. (2010) Vitamin D and Cancer. In: Bioactive Compounds and Cancer. J. Milner and D. Romognolo Ed(s). Pp.357-386. Humana Press, 0.
  • Fleet, J.C. (2007) Using genomics to understand intestinal biology. J Physiol Biochem. 63:83-96.

Learning

NUTR 59000Nutrition and Genetics: 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.
NUTR 59000 AAdvanced Presentation Skills: This class teaches students how to organize and prepare a extended research presentation. Students are taught how to use an outline to organize their topic, how to use graphic tools to develop presentation materials, and how to present material for a 40 minute seminar on a research topic relevant to Nutrition Science. Typically offered Spring.
NUTR 59000 BAdvanced Writing Skills for Graduate Students: This class teaches how to organize and write a critical, literature-based review of the scientific evidence on a dissertation-relevant topic in nutrition science.
NUTR 60500Nutritional Biochemistry and Physiology I: 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: Principles of molecular regulation, cell biology of the intestine, nutrient transport, carbohydrate metabolism, and mineral metabolism. Typically offered Fall.
NUTR 69400Presentation Skills for Graduate Students: This course teaches graduate students the basics for how to prepare and present nutrition research for a scientific audience. Students prepare two presentations that are fundamental for working researchers: a 12 minute oral presenation and a poster presentation. Typically offered Spring.

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