Contribution of Zranb3 to normal and stressed hematopoiesis
Contribution of Zranb3 to normal and stressed hematopoiesis
批准号:
10668267
负责人:
Saul Kushinsky
金额:
$5.27万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-07-01 至 2024-06-30
关键词:
AccelerationApoptosisB-Cell LymphomasBiochemicalBiologicalBloodBlood CellsBone MarrowBone Marrow CellsBone marrow failureCD34 geneCancer cell lineCell DeathCellsCellular StressCessation of lifeDNADNA DamageDNA Sequence AlterationDNA biosynthesisDNA replication forkDNA strand breakDataDefectDevelopmentDoctor of PhilosophyEducationEmergency SituationEvaluationFailureFamily memberGenesGenomeGenomic InstabilityGoalsHematologyHematopoiesisHematopoieticHematopoietic SystemHematopoietic stem cellsHumanInvestigationKnowledgeLifeLymphoidMentorsMusMyelogenousPathway interactionsPhysiciansPhysiologicalPopulationProcessProliferatingProteinsReportingRoleScientistSourceStem Cell DevelopmentStimulusStressTestingTrainingUniversitiesbiological adaptation to stresscancer cellcareer developmentdefined contributionexperimental studygene conservationin vivoin vivo Modelinsightknock-downmouse modelpreferencepreservationpreventprogramsprotective effectrepairedreplication stressresponseskillsstem cell functionstem cell proliferationtranscriptome sequencing
中文摘要
项目总结
英文摘要
Project Summary
Hematopoiesis, the process by which hematopoietic stem and progenitor cells (HSPCs) in the bone marrow
produce all mature blood cells for the hematopoietic system, is required for life. HSPCs are particularly prone to
DNA replication stress due to their high rates of replication during normal hematopoiesis and certainly during
bursts of proliferation from stress-induced/emergency hematopoiesis. DNA replication stress that is not properly
resolved is postulated to contribute to genomic instability and cell death, ultimately leading to HSPC defects,
deficiencies and/or bone marrow failure. Yet, the proteins that mitigate such stress in HSPCs remain largely
uncharacterized. Understanding the proteins that respond to DNA replication stress in HSPCs is essential to
understanding how HSPC development and function is protected throughout a lifetime. Recently, Smarcal1 and
Zranb3, two proteins with the same biochemical activity of fork reversal and remodeling, were determined in
human cancer cells to respond to DNA replication stress and prevent DNA replication fork collapse, but their role
in vivo and in hematopoietic cells remained unexplored. The Eischen lab discovered that while Smarcal1 is not
required for normal hematopoiesis, it is essential for HSPCs during stressed/emergency hematopoiesis.
Currently, little is known about Zranb3 in vivo, as well as whether the functions of Smarcal1 and Zranb3 are
redundant in vivo in hematopoietic cells. Our preliminary data suggest Zranb3 may be essential for HSPCs and
its functions are non-redundant with Smarcal1 in vivo. Therefore, we hypothesize Zranb3 is an essential
component of the DNA replication stress response in HSPCs and significantly contributes to their proliferation
and survival. To test this hypothesis, we will use mouse models and both mouse and human primary
hematopoietic cells. In Aim 1, we propose to investigate the requirements of Zranb3 to normal hematopoiesis
and the mechanism involved. In Aim 2, we will investigate the contribution of Zranb3 to DNA replication stress-
induced during stressed/emergency hematopoiesis. Results from the proposed experiments will significantly
increase understanding of the DNA replication stress response that protects hematopoietic cells during normal
and stressed hematopoiesis and prevents hematopoietic cell failure.
The MD/PhD program at Thomas Jefferson University provides challenging, comprehensive training that
will allow me to fulfill the goals of this application and become a successful independent physician-scientist. My
training will include the development of many skills and an increase of knowledge through multiple approaches
supported by my mentor, thesis committee, and other scientists. The educational and career development
objectives outlined in this proposal will help me fulfill my goal of becoming a successful, independent physician-
scientist focused on hematology.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Contribution of Zranb3 to normal and stressed hematopoiesis
-
批准号:10066914
-
项目类别:
-
资助金额:$4.68万
-
财政年份:2020
-
负责人:Saul Kushinsky
-
依托单位:
Contribution of Zranb3 to normal and stressed hematopoiesis
-
批准号:10434720
-
项目类别:
-
资助金额:$5.18万
-
财政年份:2020
-
负责人:Saul Kushinsky
-
依托单位:
Contribution of Zranb3 to normal and stressed hematopoiesis
-
批准号:10165460
-
项目类别:
-
资助金额:$4.73万
-
财政年份:2020
-
负责人:Saul Kushinsky
-
依托单位:
国内基金
海外基金
登录
查看更多内容
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
-
批准号:LBY21H010001
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2020
-
负责人:郑绪阳
-
依托单位:
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
-
批准号:81703335
-
项目类别:青年科学基金项目
-
资助金额:20.0万元
-
批准年份:2017
-
负责人:卫高菲
-
依托单位:
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
-
批准号:81670594
-
项目类别:面上项目
-
资助金额:58.0万元
-
批准年份:2016
-
负责人:陈昊
-
依托单位:
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
-
批准号:81470791
-
项目类别:面上项目
-
资助金额:73.0万元
-
批准年份:2014
-
负责人:董家鸿
-
依托单位:
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
-
批准号:81301123
-
项目类别:青年科学基金项目
-
资助金额:23.0万元
-
批准年份:2013
-
负责人:王海莲
-
依托单位:
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
-
批准号:81101529
-
项目类别:青年科学基金项目
-
资助金额:22.0万元
-
批准年份:2011
-
负责人:陈雪芹
-
依托单位:
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
-
批准号:39500043
-
项目类别:青年科学基金项目
-
资助金额:9.0万元
-
批准年份:1995
-
负责人:梁克
-
依托单位: