Live cell reporters of genetic changes in stiff vs soft surroundings - Causes & Consequences

僵硬与柔软环境中遗传变化的活细胞报告 - 原因

基本信息

  • 批准号:
    10092733
  • 负责人:
  • 金额:
    $ 91.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Project Abstract Live cell reporters of genetic changes in stiff vs soft surroundings – causes & consequences Solid tumors are often palpably stiff and more constrained in 3D growth than ‘liquid’ hematopoietic tumors. Extensive sequencing of dozens of cancer types further indicates that solid tumors within stiff tissues exhibit many more genetic changes than liquid and soft-tissue tumors [Pfeifer 2017]. Our first hypothesis is a mechano-genetics hypothesis, namely genetic changes are caused in part by the mechanics of the tumor or tissue micro-environment. A key limitation of current sequencing methods is that they require killing cells to isolate the DNA, which prevents tracking a cell before, during, and after a genetic change. A new method is needed to track genetic changes in living cells under diverse biophysical stresses. Our second hypothesis is that gene editing can be used to enable tracking some changes in the genetics of single cells in real-time. Preliminary results from a new approach already support both hypotheses. RFP (red fluorescent protein) is fused to a single allele of an abundant constitutive gene in cancer cells or normal cells. For appropriate genes, we find that RFP-neg cells have lost all or part of the edited chromosome, using methods that range from single cell DNA-seq to allele-specific PCR. For the one edited chromosome that has been studied most deeply (of three), the RFP-neg cells divide and pass on the genetic change, and they also exhibit a ‘go-and-grow’ phenotype consistent with partial loss of a key tumor suppressor. In solid tumor xenografts that start with freshly sorted RFP-pos cells, the fraction of RFP-neg cells scales strongly with the number of cell divisions, unlike 2D cultures, and 3D imaging further shows that (i) dividing cells are flattened in vivo, and (ii) interphase nuclei with high curvature tend to rupture and exhibit high DNA damage. In reductionist 3D culture studies, confinement and constriction likewise increase GFP-neg cell numbers. The preliminary results directly support our mechano-genetics hypothesis. We will replicate and extend our preliminary results both in vitro and in vivo with the ultimate goals of identifying mechanically modulated pathways of chromosome loss and consequences for phenotype. For relevance to patients, the in vivo studies will include liver cancer patient derived xenografts (PDX) that are gene edited and grown in liver as well as softer and stiffer sites.
项目摘要

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Dennis E. Discher其他文献

How deep cells feel: Mean-field Computations and Experiments
  • DOI:
    10.1016/j.bpj.2008.12.3320
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Amnon Buxboim;Shamik Sen;Dennis E. Discher
  • 通讯作者:
    Dennis E. Discher
Small fat droplets interact with structural filaments in macrophages with cytoskeletal dysfunction contributing to perturbed phagocytosis and migration
  • DOI:
    10.1016/j.bpj.2022.11.2223
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Michael P. Tobin;Irena L. Ivanovska;Dennis E. Discher
  • 通讯作者:
    Dennis E. Discher
Solid Tumor Cures by Complete Disruption of the CD47:SIRPα Macrophage Checkpoint, Tumor Opsonization, and ‘Phagocytic Feedback’
  • DOI:
    10.1016/j.bpj.2020.11.743
  • 发表时间:
    2021-02-12
  • 期刊:
  • 影响因子:
  • 作者:
    Lawrence J. Dooling;Jason C. Andrechak;Brandon H. Hayes;Siddhant Kadu;Ruby Pan;Michael P. Tobin;Manasvita Vashisth;Dennis E. Discher
  • 通讯作者:
    Dennis E. Discher
Nuclear curvature, rupture, and lamin regulation: relations to tumor proliferation and cancer survival
  • DOI:
    10.1016/j.bpj.2021.11.2134
  • 发表时间:
    2022-02-11
  • 期刊:
  • 影响因子:
  • 作者:
    Irena L. Ivanovska;Dennis E. Discher
  • 通讯作者:
    Dennis E. Discher
Optimized Quantitation from Proteomic Datasets - Application to Lamin Knockdown and Isoform Modulation During Stem Cell Differentiation
  • DOI:
    10.1016/j.bpj.2010.12.470
  • 发表时间:
    2011-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Joe Swift;Takamasa Harada;Jae-Won Shin;Hsin-Yao Tang;David W. Speicher;Dennis E. Discher
  • 通讯作者:
    Dennis E. Discher

Dennis E. Discher的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Dennis E. Discher', 18)}}的其他基金

Mechanics of Cells & Tissues impact Chromosome Instability & Phagocytic Interactions
细胞力学
  • 批准号:
    10626283
  • 财政年份:
    2023
  • 资助金额:
    $ 91.66万
  • 项目类别:
Live cell reporters of genetic changes in stiff vs soft surroundings - Causes & Consequences
僵硬与柔软环境中遗传变化的活细胞报告 - 原因
  • 批准号:
    10594852
  • 财政年份:
    2021
  • 资助金额:
    $ 91.66万
  • 项目类别:
Live cell reporters of genetic changes in stiff vs soft surroundings - Causes & Consequences
僵硬与柔软环境中遗传变化的活细胞报告 - 原因
  • 批准号:
    10373929
  • 财政年份:
    2021
  • 资助金额:
    $ 91.66万
  • 项目类别:
Live cell reporters of genetic changes in stiff vs soft surroundings - Causes & Consequences
僵硬与柔软环境中遗传变化的活细胞报告 - 原因
  • 批准号:
    10608069
  • 财政年份:
    2021
  • 资助金额:
    $ 91.66万
  • 项目类别:
Live cell reporters of genetic changes in stiff vs soft surroundings - Causes & Consequences
僵硬与柔软环境中遗传变化的活细胞报告 - 原因
  • 批准号:
    10737802
  • 财政年份:
    2021
  • 资助金额:
    $ 91.66万
  • 项目类别:
Nuclear Mechanics varies with Tissue Mechanics & Regulates Cytoskeleton
核力学随组织力学而变化
  • 批准号:
    8928873
  • 财政年份:
    2015
  • 资助金额:
    $ 91.66万
  • 项目类别:
Project 3: Nuclear Rheology & Stability in Cancer
项目3:核流变学
  • 批准号:
    8866927
  • 财政年份:
    2015
  • 资助金额:
    $ 91.66万
  • 项目类别:
Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology
肝癌:癌前硬化、膜转导、
  • 批准号:
    9091502
  • 财政年份:
    2015
  • 资助金额:
    $ 91.66万
  • 项目类别:
PSOC@Penn Education and Outreach
PSOC@Penn 教育和外展
  • 批准号:
    8866929
  • 财政年份:
    2015
  • 资助金额:
    $ 91.66万
  • 项目类别:
Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology
肝癌:癌前硬化、膜转导、
  • 批准号:
    8866921
  • 财政年份:
    2015
  • 资助金额:
    $ 91.66万
  • 项目类别:

相似海外基金

Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
  • 批准号:
    502556
  • 财政年份:
    2024
  • 资助金额:
    $ 91.66万
  • 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
  • 批准号:
    10659303
  • 财政年份:
    2023
  • 资助金额:
    $ 91.66万
  • 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
  • 批准号:
    10674405
  • 财政年份:
    2023
  • 资助金额:
    $ 91.66万
  • 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
  • 批准号:
    10758772
  • 财政年份:
    2023
  • 资助金额:
    $ 91.66万
  • 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
  • 批准号:
    10676499
  • 财政年份:
    2023
  • 资助金额:
    $ 91.66万
  • 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
  • 批准号:
    2748611
  • 财政年份:
    2022
  • 资助金额:
    $ 91.66万
  • 项目类别:
    Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
  • 批准号:
    22K05630
  • 财政年份:
    2022
  • 资助金额:
    $ 91.66万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
  • 批准号:
    10532032
  • 财政年份:
    2022
  • 资助金额:
    $ 91.66万
  • 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
  • 批准号:
    10525070
  • 财政年份:
    2022
  • 资助金额:
    $ 91.66万
  • 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
  • 批准号:
    10689017
  • 财政年份:
    2022
  • 资助金额:
    $ 91.66万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了