项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

REDDY, MICHAEL K

项目受资助机构

UNIVERSITY OF MASSACHUSETTS AMHERST

项目编号

3R01GM111706-01S1

立项年度

2015

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

35628.00美元

学科

GENETICS

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

CHIEN, PETER

参与机构

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

项目标书摘要：DESCRIPTION (provided by applicant): Bacteria use energy dependent proteases to respond to stressful conditions. These proteases serve a dual role: destroying aberrant, potentially toxic, damaged proteins and generating stress responsive signals through degradation of regulatory factors. Cells often arrest replication in response to stress, but how regulated proteolysis contributes to cell cycle arrest in bacteria is currently poorly understood. This proposal addresses how stress related proteases target replication factors using a combination of biochemical, genetic and proteomic approaches, specifically focusing on proteases and replication factors from the model bacteria Caulobacter crescentus. Aims 1 and 2 determine how misfolded proteins generated during proteotoxic stress directly stimulate the Lon protease to destroy the replication initiator DnaA and cause growth arrest during stress. Aims 3 and 4 focus on how partial processing of the clamp loader subunit DnaX by the ClpXP protease is critical for replication stress tolerance during DNA damage. Because these proteases and replication factors are highly conserved throughout all bacteria, these results will impact our general understanding of replication, proteolysis, and stress tolerance. The critical role of these proteases in bacterial virulence and pathogenicity, together with the universal requirement for these proteases in bacterial stress responses, suggests that they are excellent targets for development of new antibiotic strategies that are of immediate human health need.