Blair B. Madison, Ph.D.

Assistant Professor
Internal Medicine
Gastroenterology

Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program

  • 314-362-9050

  • 8124

  • bmadison@dom.wustl.edu

  • Utilize functional genomics to identify new genes and pathways that regulate epithelial transformation in the intestine

Research Abstract:

The overarching goal of my research is to pursue functional genomics to identify new genes and pathways that regulate epithelial transformation in the intestine. Mouse models for the study of cancer have traditionally focused on the examination of one gene at a time, typically using mice with single heritable mutations. Because technologies have moved on to examine the effects of somatic (non-heritable) mutations in adult mice, there has been an enhanced ability to focus on specific tissues in adult animals (e.g. using Cre-Lox approaches). Now, with new genome editing technologies, one can examine multiple genes simultaneously in a single adult animal. In conjunction with random mutagenesis tools (e.g. transposons), the genetics of cancer can be explored in great detail for discovery (screens) and hypothesis-driven studies (reverse genetics). New genome editing technologies (such as CRISPR/Cas) are especially useful for studying large families of genes, or for studying multiple different genes all at once, because these techniques enable “multiplexing,” i.e. the generation of many mutations all at once. The implementation of this technology in animal models has several key benefits: 1) One can examine how cancer genes cooperate or how large gene families function in an integrated or redundant manner. Prior techniques would require the generation of each mutation in separate lines, followed by a very lengthy and laborious breeding scheme to combine each mutation. Still, examining multiple genes at once is key since cancers in humans typically arise from several “driver” mutations. 2) This technology is applicable to adult animals in somatic cells, meaning that one can mutate cells in adults, on demand (the mutation machinery can be “turned on”), in a mosaic (patchy) fashion. This also enables more accurate models, as almost all cancers arise due to the contribution from random mutations that occur in adult tissues, not from germ-line mutations. 3) This technique can be made highly specific to particular genes/loci and is completely compatible with other methodologies and approaches.

My objective is to fully exploit these new technologies (CRISPR/Cas and the Piggybac transposon) for studying micro-RNAs (miRNAs) and RNA-binding proteins and the roles of these genes in colon cancer. I’m especially interested in how mutations in miRNAs, such as Let-7, and RNA-binding proteins cooperate in the regulation of epithelial proliferation. The Let-7 pathway is likely a critical regulator, and I propose genetic experiments for comprehensive analysis of this family of miRNAs. In addition, the contribution of RNA-binding proteins to carcinogenesis is poorly understood. Lastly, I am very interested in crypt dynamics, and how mutant/aberrant crypts can pattern local microenvironments in the intestine during early phases of carcinogenesis. The nature and mechanisms of local patterning by mutant crypts and intestinal adenocarcinomas is largely unknown.

Selected Publications:

Madison BB, Dunbar L, Qiao XT, Braunstein K, Braunstein E, Gumucio DL. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 2002 Sep 6;277(36):33275-83.

Madison BB, Braunstein K, Kuizon E, Portman K, Qiao XT, Gumucio DL. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development, 2005 Jan;132(2):279-89.

Madison BB, McKenna L, Dolson D, Epstein DJ, Kaestner K. Foxf1 and Foxl1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine. J Biol Chem. 2009 Feb 27;284(9):5936-44.

Zacharias WJ*, Madison BB*, Kretovich KE, Walton KD, Richards N, Udager AM, Li X, Gumucio DL. Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. Dev Biol. 2011 Jul 1;355(1):152-62. *Authors contributed equally. COVER IMAGE. Cited by Faculty of 1000.

Madison BB, Liu Q, Zhong X, Hahn CM, Lin N, Emmett M, Stanger BZ, Lee JS, Rustgi AK. LIN28B regulates growth and tumorigenesis of the intestinal epithelium via Let-7. Genes and Development. 15 October 2013; Vol. 27, No. 20.

Madison BB, Jeganathan A, Mizuno R, Winslow MM, Castells A, Cuatrecasas M, Rustgi AK, Let-7 Represses Carcinogenesis and a Stem Cell Phenotype in the Intestine via Regulation of Hmga2. PLoS Genetics, 2015 Aug 5;11(8).

Last Updated: 8/26/2015 9:09:57 AM

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