DNA-Protein Cross-link Formation by Chimeric Bis-electrophiles
嵌合双亲电子试剂形成 DNA-蛋白质交联
基本信息
- 批准号:2346706
- 负责人:
- 金额:$ 55.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Standard Grant
- 财政年份:2024
- 资助国家:美国
- 起止时间:2024-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professor Marc Greenberg of Johns Hopkins University and his research team are studying the development of molecules for the selective formation of DNA-protein crosslinks (DPCs). DPCs are a cytotoxic form of DNA damage that potently block replication and transcription. Despite their biological significance, DPCs are often overshadowed by other forms of damage, such as DNA-DNA interstrand crosslinks (ICLs). The development of these molecules could be useful for studying DPC formation in the test tube, in cells and possibly even organisms. Selective DPC formation would enable scientists to study how such cytotoxic lesions are repaired and determine the consequences of their formation on processes involved in genetic expression. These molecules could be especially useful in the complex environment of cells, where the formation of mixtures makes it particularly difficult to elucidate the consequences of individual chemical products. This project will provide students with broad training in several research areas, including synthetic organic chemistry, biochemistry, and cell biology. The students that obtain training while contributing to this project, will include those from groups that have historically been underrepresented in the sciences.Under this award, the Greenberg laboratory will focus synthetic efforts on bis-electrophiles that take advantage of the high reactivity of nitrogen mustards to rapidly alkylate DNA. However, one of the highly reactive chloroethyl groups will be replaced with a more selective electrophile that is designed to preferentially react with the side-chain amino group of lysines. In this way, the formation of monoalkylation products that account for the majority of nitrogen mustard reactivity will be disfavored. Furthermore, the selectivity of the electrophile to form DPCs over ICLs will be determined. Selective DPC formation will be tested in nucleosome core particles, as well as in cells. Preferential DPC formation compared to ICLs will be probed using various cell lines that are deficient in repair of one lesion family. For instance, it is hypothesized that cells lacking SPRTN, a protease that initiates DPC repair, will be hypersensitive to the molecules. Selective DPC formation in cells that lack SPRTN would enable the exploration of alternative DPC repair systems. Studies with these bis-electrophiles may provide the foundation for the discovery of therapeutic agents that act by forming DPCs in targeted cellular loci.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
在化学系生命过程化学(CLP)项目的支持下,约翰霍普金斯大学的Marc Greenberg教授和他的研究小组正在研究用于选择性形成DNA-蛋白质交联(DPC)的分子的发展。DPC是DNA损伤的细胞毒性形式,其有效地阻断复制和转录。尽管它们具有生物学意义,但DPC经常被其他形式的损伤所掩盖,例如DNA-DNA链间交联(ICL)。这些分子的发展可能有助于研究DPC在试管、细胞甚至生物体中的形成。选择性DPC的形成将使科学家能够研究这种细胞毒性损伤是如何修复的,并确定它们的形成对基因表达过程的影响。这些分子在细胞的复杂环境中可能特别有用,其中混合物的形成使得特别难以阐明单个化学产物的后果。该项目将为学生提供几个研究领域的广泛培训,包括合成有机化学,生物化学和细胞生物学。在为该项目做出贡献的同时获得培训的学生将包括那些来自历史上在科学领域代表性不足的群体的学生。根据该奖项,格林伯格实验室将专注于双亲电体的合成工作,这些亲电体利用氮分子的高反应性快速烷基化DNA。然而,其中一个高度反应性的氯乙基基团将被替换为更有选择性的亲电试剂,该亲电试剂被设计为优先与赖氨酸的侧链氨基基团反应。以这种方式,将不利于形成占氮芥反应性的大部分的单烷基化产物。此外,将确定亲电试剂形成DPC相对于ICL的选择性。将在核小体核心颗粒以及细胞中测试选择性DPC形成。与ICL相比,优先DPC形成将使用一种损伤家族修复缺陷的各种细胞系进行探测。例如,假设缺乏SPRTN(一种启动DPC修复的蛋白酶)的细胞将对这些分子过敏。在缺乏SPRTN的细胞中选择性DPC形成将使得能够探索替代DPC修复系统。对这些双亲电体的研究可能为发现通过在目标细胞位点形成DPC发挥作用的治疗剂提供基础。该奖项反映了NSF的法定使命,并通过使用基金会的知识价值和更广泛的影响进行评估而被认为值得支持。审查标准。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marc Greenberg其他文献
Does Orthopaedic Resident Pelvis Fluoroscopy Knowledge improve with testing with a Novel Pelvis Model and Educational website?
- DOI:
10.1007/s00264-024-06393-0 - 发表时间:
2024-12-23 - 期刊:
- 影响因子:2.600
- 作者:
Henry T. Shu;Diane Ghanem;Justin E. Hellwinkel;Nicholas J. Tucker;Benjamin D. Pesante;Marc Greenberg;Chima D. Nwankwo;Babar Shafiq;Cyril Mauffrey - 通讯作者:
Cyril Mauffrey
A Five-Year Cost-Utility Analysis Comparing Synthetic Cage Versus Allograft Use in Anterior Cervical Discectomy and Fusion Surgery for Cervical Spondylotic Myelopathy
颈前路椎间盘切除术和融合手术治疗脊髓型颈椎病中合成笼与同种异体移植的五年成本效用分析比较
- DOI:
10.1097/brs.0000000000004526 - 发表时间:
2022 - 期刊:
- 影响因子:3
- 作者:
M. Raad;Amy L. Xu;Carlos D. Ortiz;M. Marrache;Wesley M. Durand;Marc Greenberg;Amit Jain - 通讯作者:
Amit Jain
Optimizing bone health for the prevention of revision adult spinal deformity surgery: a break-even analysis
- DOI:
10.1007/s43390-025-01070-7 - 发表时间:
2025-04-11 - 期刊:
- 影响因子:1.800
- 作者:
Andrew H. Kim;William ElNemer;Marc Greenberg;Micheal Raad;Khaled M. Kebaish - 通讯作者:
Khaled M. Kebaish
Pain Self-Efficacy (PSEQ) score of <22 is associated with daily opioid use, back pain, disability, and PROMIS scores in patients presenting for spine surgery
<22 的疼痛自我效能(PSEQ)评分与脊柱手术患者的日常阿片类药物使用、背痛、残疾和 PROMIS 评分相关。
- DOI:
10.1016/j.spinee.2022.12.015 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:4.700
- 作者:
Kevin C. Mo;Arjun Gupta;Jonathan Movsik;Oscar Covarrubius;Marc Greenberg;Lee H. Riley;Khaled M. Kebaish;Brian J. Neuman;Richard L. Skolasky - 通讯作者:
Richard L. Skolasky
Racial disparities in lower extremity orthopaedic injuries presenting to U.S. emergency departments from 2010 to 2020
2010 年至 2020 年美国急诊科就诊的下肢骨科损伤的种族差异
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0.6
- 作者:
Arjun Gupta;Priya Singh;Daniel Badin;Kevin C. Mo;Marc Greenberg;F. Musharbash;Alice J. Hughes;J. Ficke;A. Aiyer - 通讯作者:
A. Aiyer
Marc Greenberg的其他文献
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{{ truncateString('Marc Greenberg', 18)}}的其他基金
Selective Detection and Quantification of DNA Lesions
DNA 损伤的选择性检测和定量
- 批准号:
0956466 - 财政年份:2010
- 资助金额:
$ 55.5万 - 项目类别:
Continuing Grant
Development and Application of Oligonucleotide Synthesis Methods
寡核苷酸合成方法的开发及应用
- 批准号:
0245625 - 财政年份:2002
- 资助金额:
$ 55.5万 - 项目类别:
Continuing Grant
Development and Application of Oligonucleotide Synthesis Methods
寡核苷酸合成方法的开发及应用
- 批准号:
9732843 - 财政年份:1998
- 资助金额:
$ 55.5万 - 项目类别:
Continuing Grant
Development and Application of Solid Phase Oligonucleotide Synthesis Supports
固相寡核苷酸合成载体的开发及应用
- 批准号:
9424040 - 财政年份:1995
- 资助金额:
$ 55.5万 - 项目类别:
Standard Grant
Research Experiences for Undergraduates in Chemical Synthesis at Colorado State University
科罗拉多州立大学化学合成本科生研究经历
- 批准号:
9322087 - 财政年份:1994
- 资助金额:
$ 55.5万 - 项目类别:
Continuing Grant
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