Adayabalam Balajee Abstract
Project Title: Biological Effects of Low Dose Radiation in 3D Tissues: Role of Genetic
and Epigenetic Mechanisms
DOE Program Notice Number: DE-FG02-06ER06-10
Applicant Institution: Columbia University Medical Center,
Center for Radiological Research,
Department of Radiation Oncology,
630 West, 168th Street,
VC-11, Room 239,
New York, NY 10032.
Principal Investigator: Adayabalam S. Balajee, M.Phil., Ph.D.,
Center for Radiological Research,
Department of Radiation Oncology,
College of Physicians and Surgeons,
Columbia University Medical Center,
VC-11, Room 239,
630 West, 168th Street,
New York, NY.
Tel: 212-342-6838
Fax: 212-305-3229
Performance Site: Same as above
Collaborator: Dr. Jean-Luc Ravanat, Ph.D.,
Lesions des Acides Nucleiques,
DRFMC/SCIB, CEA Grenoble,
17 rue des Martyrs, F38054 Grenoble,
Cedex 9, France
Tel: 33 (0) 438 784797
Fax: 33 (0) 438 785090
DOE/Office of Science Program Office: Office of Biological and Environmental Research
(BER), Chicago Service Center
DOE/Office of Science Program Office Technical Contact: Deb Greenawalt
Adayabalam S. Balajee
Project Title: Biological Effects of Low Dose Radiation in 3D Tissues: Role of Genetic
and Epigenetic Mechanisms (Principal Investigator: Adayabalam S.
Balajee)
Abstract:
It is increasingly realized that human exposure either to an acute low dose or multiple chronic low
doses of low LET radiation has the potential to cause different types of cancer. Therefore, the
central theme of research for DOE and NASA is focused on understanding the molecular
mechanisms and pathways responsible for the cellular response to low dose radiation which
would not only improve the accuracy of estimating health risks but also help in the development
of predictive assays for low dose radiation risks associated with tissue degeneration and cancer.
The principal hypothesis for this proposal is that the biological effects of low doses of low
LET radiation involve a combination of genetic and epigenetic changes and that the severity of
genetic and epigenetic alterations predicts the outcome of genomic instability and cancer
susceptibility in humans. This hypothesis will be tested at two different levels (genetic and
epigenetic) in two different tissue model systems: human 3-dimenisonal tissue constructs and
intact mouse tissues. The genetic component will include cellular and biochemical analysis of cell
survival, DNA damage signaling, repair or misrepair and apoptosis in different human 3D tissue
constructs and mouse tissues after low (less than or equal to 0.1Gy) and high (0.5Gy-2.5Gy)
doses of low LET radiation (X-rays, g-rays and protons). Epigenetic component will include the
genome wide analysis of DNA methylation and histone modifications in different human 3D tissue
constructs and mouse tissues as a function of radiation dose and genotype. The proposal is
comprised of three specific aims: (I) To determine the DNA damage signaling and repair
responses in human and mouse tissue microenvironment as a function of radiation dose and
time; (II) To determine the low LET radiation induced epigenetic alterations (DNA methylation and
histone modifications) as a function of dose and (III) To evaluate the role of phosphatidylinositol 3
kinase like kinases (ataxia telangiectasia mutated and DNA dependent protein kinase) in low LET
radiation induced epigenetic alterations. Systematic analysis of genetic and epigenetic effects as
a function of radiation dose and genotype is expected to provide mechanistic insights into
biological effects of low LET radiation exposure. Additionally, the proposed study is expected to
provide epigenetic markers for radiation exposure in tissue microenvironment which will be of use
for low dose radiation risk assessment in humans.
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