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Research Interest:
One of my main
research interests is to understand the early development of the
immune system, particularly the assembly and diversification of
antigen receptor genes. Two of these processes, also known as VDJ
recombination and somatic hypermutation, allow for the generation of
hundreds of millions of different antigen receptors and by doing so
they enable our organism to recognize virtually any foreign antigen.
Such diversity in recognition is essential in combating all
microbial infections. My work on this topic generated three first
author articles that provide a mechanistic explanation for the
non-random generation of the primary antigen receptor repertoire and
open new directions towards the experimental investigations on the
physiological role of restricted combinatorial diversity in the
adaptive immune response. A fourth first author paper was the first
one to define the promoter of the AICDA gene. The protein encoded by
this gene controls two important processes for our immune system:
somatic hypermutation and class-switch recombination. Better
understanding of the tight regulation of AICDA has potential
application in the field of vaccinology.
A second area of
interest is related to the surveillance and repair of DNA damage.
VDJ recombination, somatic hypermutation and class-switch
recombination all involve modifications and/or cleavage of the DNA
that encode the immunoglobulin genes. Therefore the same proteins
that monitor DNA damage and help maintain genomic stability by
repairing DNA broken ends also play a crucial role in these
processes. In collaboration with three independent laboratories from
the National Cancer Institute, NIH and Mayo Clinic I investigated
the way our cells harness the various mechanisms of genomic
rearrangements to make a productive immune system while avoiding the
potentially dangerous side effects that emerge when these processes
go wrong. The findings of these studies have been included in three
papers published in Science, PNAS and Journal of Cell Biology.
A third major
research interest is to define micro RNA expression profiles in
order to identify "biological signatures" of colon and esophageal
cancer and to identify the target genes of this newly discovered
class of RNA
Finally, a
fourth area of interest is to identify pathways underlying
inflamatory bowel disease-associated neoplastic transformation.
Selected
Publication:
- Celeste A,
Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT,
Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E,
Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus
M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner
WM, Nussenzweig MC, Nussenzweig A. Genomic instability in mice
lacking histone H2AX. Science. 2002 May 3;296(5569):922-7
- Olaru A,
Patterson D, Villey I and Livak F DNA-RAG protein interactions
in the control of selective D gene utilization in the TCRb locus
J Immunol. 2003 Oct 1;171(7):3605-11.
- Olaru A,
Patterson D, Cai H and Livak F. Recombination signal sequence
variations and the mechanism of patterned T-cell receptor-b
locus rearrangementMol Immunol. 2004 Mar;40(16):1189-201
- Ward IM,
Reina-San-Martin B, Olaru A, Minn K, Tamada K, Lau JS,
Cascalho M, Chen L, Nussenzweig A, Livak F, Nussenzweig MC, Chen
J. 53BP1 is required for class switch recombination. J Cell
Biol. 2004 May 24;165(4):459-64.
- Tabrizifard
S, Olaru A, Plotkin J, Fallahi-Sichani M, Livak F, Petrie
HT. Analysis of transcription factor expression during discrete
stages of postnatal thymocyte differentiation. J Immunol. 2004
Jul 15;173(2):1094-102.
- Yadav A,
Olaru A, Saltis M, Setren A, Cerny J, Livak F.
Identification of a ubiquitously active promoter of the murine
activation-induced cytidine deaminase (AICDA) gene.Mol Immunol.
2005 Jul 5;
- Olaru A,
Petrie HT, Livak F. Beyond the 12/23 rule of VDJ recombination
independent of the Rag proteins.J Immunol. 2005 May
15;174(10):6220-6.
- Vacchio MS,
Olaru A, Nakamura A, Bonner W, Livak F, Hodes RJ. ATM is
required for efficient TCRα recombination in CD4+CD8+
thymocytes. Proc Natl Acad Sci U S A. 2007 Apr
10;104(15):6323-8.
- Jin Z ,
Olaru A, Yang J, Sato F, Cheng Y, Kan T, Mori Y, Mantzur C,
Paun B, Hamilton JP, Ito T, Wang S, David S, Agarwal R, Beer DG,
Abraham JM and Meltzer SJ Hypermethylation of Tachykinin-1 is
Associated with a Poor Prognosis in Human Esophageal Squamous
Cell Carcinoma. Clinical Cancer Research
2007 Nov 1;13(21):6293-300.
- Jin Z ,
Mori Y, Hamilton JP, Olaru A , Sato F , Yang J , Ito T ,
Kan T, Agarwal R , Meltzer SJ. Hypermethylation of the
somatostatin promoter is a common, early event in human
esophageal carcinogenesis. Cancer
2008 Jan 1;112(1):43-9.
- Jin Z,
Cheng Y, Olaru A, Kan T, Yang J, Paun B, Ito T, Hamilton
JP, David S, Agarwal R, Selaru FM, Sato F, Abraham JM, Beer DG,
Mori Y, Shimada Y, Meltzer SJ.
Promoter hypermethylation of
CDH13 is a common, early event in human esophageal
adenocarcinogenesis and correlates with clinical risk factors.
Int J Cancer. 2008 Aug 26. [Epub ahead of print]
- Selaru FM,
Olaru AV, Kan T, David S, Cheng Y,
Mori Y, Yang J, Paun B, Jin
Z, Agarwal R, Hamilton JP, Abraham
J, Georgiades C, Alvarez H,
Vivekanandan P, Yu W, Maitra A,
Torbenson M, Thuluvath PJ, Gores
GJ, LaRusso NF, Hruban R, Meltzer
SJ. MicroRNA-21 is overexpressed in human
cholangiocarcinoma and regulates programmed cell death 4 and
tissue inhibitor of metalloproteinase 3
Hepatology. 2009
May;49(5):1595-601.
- Kan T, Sato
F, Ito T, Matsumura N, David S, Cheng Y, Agarwal R, Paun BC, Jin
Z, Olaru AV, Selaru FM, Hamilton JP, Yang J, Abraham JM,
Mori Y, Meltzer SJ.
The
miR-106b-25 polycistron, activated by genomic amplification,
functions as an oncogene by suppressing p21 and Bim.
Gastroenterology. 2009
May;136(5):1689-700.
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