- Regulation of gene expression by growth factors in animal cells
- Imaging of gene expression in vivo
- Applications of aptamers to medical technology
Growth factors regulate proliferation and cellular activities that result in coordinated growth and differentiation of animal tissues. To achieve their effects, growth factors regulate gene expression and thus the production of new proteins. Proteins that are secreted are often involved in coordinating cell growth in multicellular tissues. Dr. Nilsen-Hamilton has discovered several secreted proteins and their genes that are regulated by growth factors. The research team is exploring the means by which these genes are regulated by growth factors.
The group discovered a unique fibroblast growth factor response element (FRE) in the mrp3 gene promoter. The FRE is also found in the promoters of many metalloproteinases that are important for cancer cell movement during metastasis. They have also found that the mrp/plf genes are expressed during wound healing and also in some fetal tissues. Mrp3 is the main mrp/plf that is expressed in the wound.
Uterocalin is another secreted protein that is regulated by growth factors. It is an acute phase protein, produced by the liver, lungs and other epithelial tissues in response to stress such as occurs with infections. Uterocalin is also produced by the uterus around birth and in the mammary gland during involution after the young have stopped suckling. The protein is a lipocalin and may be involved in protection from infections by microbes during reproduction. A higher expression of this gene is also correlated with protection against breast cancer. The group is studying the protein’s function and how the gene is regulated.
To understand how growth-factor-induced genes are regulated and to identify the physiological functions of the protein products, Dr. Nilsen-Hamilton and her group are using biochemical, molecular, cellular, and developmental approaches, which include purifying the proteins, cloning the genes, determining their sequences, identifying the relevant regulatory elements, and identifying new transcriptional regulators. They are using cell cultures to express the proteins and also as “reporter” systems to study the activity of the regulatory elements of each gene. Studies of the regulation of gene activity also involve functional in vitro assays such as the electrophoretic mobility shift assay for transcription factors and in vivo studies of the levels of expression of the gene under different physiological conditions.
In fighting almost any disease the ability to detect and treat it in the early stages is critical to a successful outcome. For most diseases there are changes in gene expression and subsequent protein products that could be used for early detection.
However, disease-initiated changes often occur in the depths of our tissues. Therefore a challenge for developing new technology to fight disease is to find ways of non-invasive imaging (e.g. no biopsy or surgery) of the body’s status.
- Zhai L, Wang T, Kang K, Zhao Y, Shrotriya P, Nilsen-Hamilton M. An RNA
aptamer-based microcantilever sensor to detect the inflammatory marker, mouse
lipocalin-2. Anal Chem. 2012 Oct 16;84(20):8763-70. doi: 10.1021/ac3020643. Epub 2012 Sep 26. PubMed PMID: 22946879.
- Howk CL, Levine HA, Smiley MW, Mallapragada SK, Nilsen-Hamilton M, Oh J,
Sakaguchi DS. A mathematical model for selective differentiation of neural
progenitor cells on micropatterned polymer substrates. Math Biosci. 2012
Aug;238(2):65-79. doi: 10.1016/j.mbs.2012.04.001. Epub 2012 Apr 30. PubMed PMID: 22569338; PubMed Central PMCID: PMC3413252.
- Song X, Thalacker FW, Nilsen-Hamilton M. Synergistic and multidimensional
regulation of plasminogen activator inhibitor type 1 expression by transforming
growth factor type β and epidermal growth factor. J Biol Chem. 2012 Apr
6;287(15):12520-8. doi: 10.1074/jbc.M111.338079. Epub 2012 Feb 10. PubMed PMID: 22334677; PubMed Central PMCID: PMC3321001.
- Wang W, Bu W, Wang L, Palo PE, Mallapragada S, Nilsen-Hamilton M, Vaknin D. Interfacial properties and iron binding to bacterial proteins that promote the
growth of magnetite nanocrystals: X-ray reflectivity and surface spectroscopy
studies. Langmuir. 2012 Mar 6;28(9):4274-82. doi: 10.1021/la205074n. Epub 2012 Feb 27. PubMed PMID: 22316331.
- Wang L, Prozorov T, Palo PE, Liu X, Vaknin D, Prozorov R, Mallapragada S,
Nilsen-Hamilton M. Self-assembly and biphasic iron-binding characteristics of
Mms6, a bacterial protein that promotes the formation of superparamagnetic
magnetite nanoparticles of uniform size and shape. Biomacromolecules. 2012 Jan
9;13(1):98-105. doi: 10.1021/bm201278u. Epub 2011 Dec 9. PubMed PMID: 22112204.
- Kang K, Sachan A, Nilsen-Hamilton M, Shrotriya P. Aptamer functionalized
microcantilever sensors for cocaine detection. Langmuir. 2011 Dec
6;27(23):14696-702. doi: 10.1021/la202067y. Epub 2011 Sep 14. PubMed PMID:
- Saraswathi S, Sundaram S, Sundararajan N, Zimmermann M, Nilsen-Hamilton M. ICGA-PSO-ELM approach for accurate multiclass cancer classification resulting in reduced gene sets in which genes encoding secreted proteins are highly represented. IEEE/ACM Trans Comput Biol Bioinform. 2011 Mar-Apr;8(2):452-63. doi: 10.1109/TCBB.2010.13. PubMed PMID: 21233525.
- Zhao W, Grubbs CJ, Myers RK, Nilsen-Hamilton M. Parity is associated with an
expanded macrophage population in the mammary gland. Int J Oncol. 2010
Nov;37(5):1195-202. PubMed PMID: 20878067.
- Kraus GA, Gupta V, Mokhtarian M, Mehanovic S, Nilsen-Hamilton M. New effective inhibitors of the Abelson kinase. Bioorg Med Chem. 2010 Sep 1;18(17):6316-21. doi: 10.1016/j.bmc.2010.07.021. Epub 2010 Jul 14. PubMed PMID: 20674368.
- Oh J, McCloskey MA, Blong CC, Bendickson L, Nilsen-Hamilton M, Sakaguchi DS. Astrocyte-derived interleukin-6 promotes specific neuronal differentiation of
neural progenitor cells from adult hippocampus. J Neurosci Res. 2010
Oct;88(13):2798-809. doi: 10.1002/jnr.22447. PubMed PMID: 20568291; PubMed Central PMCID: PMC2981827.
- Seo YJ, Chen S, Nilsen-Hamilton M, Levine HA. A mathematical analysis of
multiple-target SELEX. Bull Math Biol. 2010 Oct;72(7):1623-65. doi:
10.1007/s11538-009-9491-x. Epub 2010 Jan 14. PubMed PMID: 20077028.
- Wang T, Hoy JA, Lamm MH, Nilsen-Hamilton M. Computational and experimental analyses converge to reveal a coherent yet malleable aptamer structure that controls chemical reactivity. J Am Chem Soc. 2009 Oct 21;131(41):14747-55. doi: 10.1021/ja902719q. PubMed PMID: 19778045.
- Boushaba K, Levine H, Hamilton MN. A mathematical feasibility argument for
the use of aptamers in chemotherapy and imaging. Math Biosci. 2009
Aug;220(2):131-42. doi: 10.1016/j.mbs.2009.05.006. Epub 2009 Jun 18. PubMed PMID: 19540245; PubMed Central PMCID: PMC2792639.
- Kraus GA, Jeon I, Nilsen-Hamilton M, Awad AM, Banerjee J, Parvin B.
Fluorinated analogs of malachite green: synthesis and toxicity. Molecules. 2008
Apr 27;13(4):986-94. PubMed PMID: 18463600.
- Levine HA, Nilsen-Hamilton M. A mathematical analysis of SELEX. Comput Biol
Chem. 2007 Feb;31(1):11-35. Epub 2007 Jan 10. PubMed PMID: 17218151; PubMed Central PMCID: PMC2374838.
- Levine HA, Smiley MW, Tucker AL, Nilsen-Hamilton M. A mathematical model for the onset of avascular tumor growth in response to the loss of p53 function.
Cancer Inform. 2007 Feb 17;2:163-88. PubMed PMID: 19458766; PubMed Central PMCID: PMC2675492.
- Boushaba K, Levine HA, Nilsen-Hamilton M. A mathematical model for the
regulation of tumor dormancy based on enzyme kinetics. Bull Math Biol. 2006
Oct;68(7):1495-526. Epub 2006 Jul 28. PubMed PMID: 16874553.
- Peters JP, Boushaba K, Nilsen-Hamilton M. A mathematical model for fibroblast
growth factor competition based on enzyme kinetics. Math Biosci Eng. 2005
Oct;2(4):789-810. PubMed PMID: 20369953.
- Cong X, Nilsen-Hamilton M. Allosteric aptamers: targeted reversibly
attenuated probes. Biochemistry. 2005 Jun 7;44(22):7945-54. PubMed PMID: 15924413.
- Determan AS, Trewyn BG, Lin VS, Nilsen-Hamilton M, Narasimhan B.
Encapsulation, stabilization, and release of BSA-FITC from polyanhydride
microspheres. J Control Release. 2004 Nov 5;100(1):97-109. PubMed PMID: 15491814.