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Molecular modulators of radiation-induced chromosome instability and hematopoietic damage

辐射引起的染色体不稳定和造血损伤的分子调节剂

基本信息

批准号：
10438851
负责人：
Zhiyuan Shen
金额：
$ 36.78万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438851
关键词：
Acute Adult Affect Animals BARD1 gene BRCA2 gene Binding Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Bone marrow failure Carcinogens Chromosomal Breaks Chromosomal Instability Chromosomal Stability Chromosomes Clonality Competence DNA Damage DNA Double Strand Break DNA Repair Development Environment Genes Genome Stability Genomics Goals Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Hypersensitivity Impairment Ionizing radiation Longevity Lymphoma Lymphomagenesis Mediating Medical Modeling Molecular Mus Natural regeneration Nature Normal tissue morphology Nucleotides Organ Pathologic Poly Adenosine Diphosphate Ribose Predisposition Process Property Proteins Radiation Radiation Tolerance Radiation exposure Radiation induced damage Recovery Role Series Site Syndrome Testing body system epigenomics experimental study genome-wide in vivo insight mature animal medical countermeasure novel radiation effect reconstitution recruit stem cell proliferation stem cells tissue regeneration tumor tumor initiation tumor progression tumorigenesis

项目摘要

Abstract The hematopoietic system is one of the organ systems most vulnerable to radiation induced short- and long- term damage. Efficient recovery from pathological or medically induced bone marrow failure is dictated by the intrinsic sensitivity of the hematopoietic stem cell and the bone marrow environment niche. Identification of molecules that affect hematopoietic recovery is essential to the development of novel medical countermeasures against radiation damage. Our preliminary studies suggested that loss of even a single copy of Bccip confers hypersensitivity of mice to radiation-induced hematopoietic syndrome and lymphomagenesis, and the recruitment of BCCIP to DNA damage sites are dependent on PARP1. We hypothesize that Bccip haploinsufficiency can sensitize the hematopoietic stem cells to radiation killing, impair the long-term competency of stem cell to reconstitute the hematopoietic system, and/or affect the bone marrow niche’s capacity to nourish hematopoiesis. In Aim 1, a series of long-term and short-term experiments will be used to determine whether Bccip haploinsufficiency enhances the killing of hematopoietic stem and progenitor cells, impair stem cells’ capacity to reconstitute the bone marrow, and diminish the ability of bone marrow niche to nourish the hematopoiesis. We also hypothesize that Bccip haploinsufficiency alters the bone marrow progenitor cell susceptibility to tumor initiation and subsequent tumor progression. In Aim 2, we will test this hypothesis by examining the tumor clonality and defining the landscapes of chromosome rearrangements in the tumors formed in wild type and Bccip haplo-insufficient mice using newly developed genomic and computational approaches. In Aim 3, we will determine the PARylaiton dependent mechanism by which BCCIP is recruited and retained at the DNA damage sites. Completion of these studies will elucidate a unique role of Bccip in modulating hematopoiesis after radiation damage and in suppressing radiation-induced tumorigenesis.

摘要