Engineering DNA Delivery Polymers using Combinatorial and Cheminformatics Methods

使用组合和化学信息学方法设计 DNA 递送聚合物

基本信息

  • 批准号:
    8416396
  • 负责人:
  • 金额:
    $ 27.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-01-12 至 2015-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to employ chemoenzymatic monomer synthesis, parallel polymer synthesis and cheminformatic modeling for the design and evaluation of polymers for transgene delivery. Gene-based strategies, designed to manipulate cellular phenotype by introducing exogenous genes, are attractive in therapeutic and functional genomics applications. Currently available non-viral (e.g. polymeric) gene delivery vectors are limited by toxicities and suffer from low efficacies. We hypothesize that a synergistic combination of rational chemoenzymatic synthesis of monomers and combinatorial polymer synthesis will lead to the rapid identification polymers with high efficacies for delivering genes to cells (Specific Aim 1). The rapid generation of transfection data will facilitate the construction of predictive Quantitative Structure-Activity Relationship (QSAR) cheminformatic models that correlate gene delivery efficacy with polymer and polyplex physicochemical properties (e.g. molecular weight, hydrophobicity, zeta potential, etc.) using Support Vector Machine (SVM) and Kernel-Partial Least Squares (K-PLS) regression (Specific Aim 2). A novel QSAR 'model- of models' approach will be developed in which, polymer physicochemical properties will first be estimated using predictive QSAR models based on monomer structure. QSAR models for transgene expression will then be generated using these estimated properties as a result of which, predictions of transgene expression efficacy will be based directly on monomer structures. In the long-term, such predictive QSAR models will aid in the rational design of high-efficacy polymeric transfection agents, which a powerful approach for non-viral gene delivery. Recognizing that polymer-mediated transgene expression suffers from low efficacies, we will employ a combination treatment approach using mediators of intracellular trafficking and transcription (chemotherapeutic enhancers), designed to enhance transgene expression in cells (Specific Aim 3). Finally, effective polymers along with chemotherapeutic enhancers will be employed for delivering genes that encode TRAIL, which selectively induces apoptosis in cancer cells, both in vitro and in vivo (Specific Aim 4). SCID mouse xenograft models will be employed to investigate recession of 22Rv1 prostate tumors, and biodistribution and toxicity of the polymer-plasmid complexes will be investigated. It is anticipated that the proposed research will result in the identification of (1) new effective polymers for non-viral gene delivery, (2) insights into polymer physicochemical factors that influence transgene delivery, (3) predictive QSAR models that will facilitate high-throughput 'in silico' identification of effective polymers, and (4) in vivo efficacy and biodistribution evaluation of polymer-based delivery. It is anticipated that this research will significantly impact gene-based therapeutics, functional genomics, and various applications that depend on high levels of transgene expression in cells. The proposed research will develop novel non-viral (polymeric) materials for gene delivery and evaluate them in vitro and in vivo. These will find significant application in gene therapy for a number of diseases and will expand therapeutic options in these cases.
描述(由申请人提供):拟议研究的总体目标是采用化学酶单体合成、平行聚合物合成和化学信息学建模来设计和评价用于转基因递送的聚合物。基于基因的策略,旨在通过引入外源基因来操纵细胞表型,在治疗和功能基因组学应用中具有吸引力。目前可用的非病毒(例如聚合物)基因递送载体受到毒性的限制并且具有低功效。我们假设单体的合理化学酶促合成和组合聚合物合成的协同组合将导致快速鉴定聚合物,其具有将基因递送至细胞的高功效(具体目标1)。转染数据的快速生成将促进预测性定量结构-活性关系(QSAR)化学信息学模型的构建,该模型将基因递送功效与聚合物和聚合复合物的物理化学性质(例如分子量、疏水性、ζ电位等)相关联。使用支持向量机(SVM)和核偏最小二乘(K-PLS)回归(具体目标2)。将开发一种新的QSAR“模型的模型”方法,其中,聚合物的物理化学性质将首先使用基于单体结构的预测QSAR模型进行估计。然后使用这些估计的性质生成转基因表达的QSAR模型,因此,转基因表达功效的预测将直接基于单体结构。从长远来看,这种预测性QSAR模型将有助于合理设计高效的聚合物转染剂,这是一种强有力的非病毒基因递送方法。认识到聚合物介导的转基因表达具有低功效,我们将采用使用细胞内运输和转录的介体(化疗增强剂)的组合治疗方法,其设计用于增强细胞中的转基因表达(具体目标3)。最后,有效的聚合物沿着化疗增强剂将用于递送编码TRAIL的基因,其在体外和体内选择性地诱导癌细胞的凋亡(特异性目的4)。将采用SCID小鼠异种移植模型研究22 Rv 1前列腺肿瘤的消退,并研究聚合物-质粒复合物的生物分布和毒性。预计拟议的研究将导致鉴定(1)用于非病毒基因递送的新的有效聚合物,(2)对影响转基因递送的聚合物物理化学因素的洞察,(3)将促进有效聚合物的高通量“计算机模拟”鉴定的预测QSAR模型,以及(4)基于聚合物的递送的体内功效和生物分布评估。预计这项研究将显著影响基于基因的治疗,功能基因组学和依赖于细胞中高水平转基因表达的各种应用。拟议的研究将开发用于基因递送的新型非病毒(聚合物)材料,并在体外和体内对其进行评估。这些将在许多疾病的基因治疗中找到重要应用,并将扩大这些情况下的治疗选择。

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 }}

Kaushal Rege其他文献

Kaushal Rege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('Kaushal Rege', 18)}}的其他基金

Near Infrared Light Activated Adhesives for Nerve Repair
用于神经修复的近红外光激活粘合剂
  • 批准号:
    10436799
  • 财政年份:
    2021
  • 资助金额:
    $ 27.78万
  • 项目类别:
Laser-Activated Nanoglues for the prevention and control of surgical site infections
激光激活纳米胶用于预防和控制手术部位感染
  • 批准号:
    10249234
  • 财政年份:
    2020
  • 资助金额:
    $ 27.78万
  • 项目类别:
Bioengineered Skin Sealants
生物工程皮肤密封剂
  • 批准号:
    10457977
  • 财政年份:
    2020
  • 资助金额:
    $ 27.78万
  • 项目类别:
DEVELOPMENT OF NOVEL AMINOGLYCOSIDE POLYMERS AND NANOPARTICLES FOR NUCLEIC ACID DELIVERY IN CHRONIC WOUNDS
开发用于慢性伤口核酸输送的新型氨基糖苷聚合物和纳米颗粒
  • 批准号:
    10009545
  • 财政年份:
    2020
  • 资助金额:
    $ 27.78万
  • 项目类别:
Bioengineered Skin Sealants
生物工程皮肤密封剂
  • 批准号:
    10226324
  • 财政年份:
    2020
  • 资助金额:
    $ 27.78万
  • 项目类别:
Bioengineered Skin Sealants
生物工程皮肤密封剂
  • 批准号:
    10676763
  • 财政年份:
    2020
  • 资助金额:
    $ 27.78万
  • 项目类别:
Bioengineered Skin Sealants
生物工程皮肤密封剂
  • 批准号:
    10053067
  • 财政年份:
    2020
  • 资助金额:
    $ 27.78万
  • 项目类别:
Photothermal Nanocomposites for Tissue Repair
用于组织修复的光热纳米复合材料
  • 批准号:
    8945323
  • 财政年份:
    2015
  • 资助金额:
    $ 27.78万
  • 项目类别:
Engineering DNA Delivery Polymers using Combinatorial and Cheminformatics Methods
使用组合和化学信息学方法设计 DNA 递送聚合物
  • 批准号:
    8602837
  • 财政年份:
    2011
  • 资助金额:
    $ 27.78万
  • 项目类别:
Engineering DNA Delivery Polymers using Combinatorial and Cheminformatics Methods
使用组合和化学信息学方法设计 DNA 递送聚合物
  • 批准号:
    8212217
  • 财政年份:
    2011
  • 资助金额:
    $ 27.78万
  • 项目类别:

相似海外基金

More sustainable biocatalytic imine reductions to chiral amines with hydrogen-driven NADPH recycling operated in batch and continuous flow
通过批量和连续流操作的氢驱动 NADPH 回收,更可持续地生物催化亚胺还原为手性胺
  • 批准号:
    2889869
  • 财政年份:
    2023
  • 资助金额:
    $ 27.78万
  • 项目类别:
    Studentship
Organoborane-catalysed approaches to biologically active amines
有机硼烷催化制备生物活性胺的方法
  • 批准号:
    EP/Y00146X/1
  • 财政年份:
    2023
  • 资助金额:
    $ 27.78万
  • 项目类别:
    Research Grant
Transforming Amines into Complex Polycyclic Molecules and Bioactive Natural Products
将胺转化为复杂的多环分子和生物活性天然产物
  • 批准号:
    2247651
  • 财政年份:
    2023
  • 资助金额:
    $ 27.78万
  • 项目类别:
    Standard Grant
Ti-catalyzed cascading hydroaminoalkylation as a route to complex functionalized amines
Ti 催化级联氢氨基烷基化作为制备复杂官能化胺的途径
  • 批准号:
    10750347
  • 财政年份:
    2023
  • 资助金额:
    $ 27.78万
  • 项目类别:
New Photocatalytic C-C Bond-Forming Reactivity of Unprotected Primary Amines
未受保护伯胺的新光催化 C-C 键形成反应
  • 批准号:
    EP/X026566/1
  • 财政年份:
    2023
  • 资助金额:
    $ 27.78万
  • 项目类别:
    Research Grant
Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines
镍与α-杂原子自由基交叉偶联级联制备位阻醇和胺
  • 批准号:
    10604535
  • 财政年份:
    2023
  • 资助金额:
    $ 27.78万
  • 项目类别:
Mining the air for amines
开采空气中的胺
  • 批准号:
    2752688
  • 财政年份:
    2022
  • 资助金额:
    $ 27.78万
  • 项目类别:
    Studentship
Towards a better understanding of the effect of the pentafluorosulfanyl group on the lipophilicity and acid/base properties of alcohols and amines
更好地了解五氟硫基对醇和胺的亲脂性和酸/碱性质的影响
  • 批准号:
    571856-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 27.78万
  • 项目类别:
    Alliance Grants
Development of Strategies for the Enantioselective Synthesis of Heterocycles and Acyclic Amines
杂环和无环胺对映选择性合成策略的发展
  • 批准号:
    10656344
  • 财政年份:
    2022
  • 资助金额:
    $ 27.78万
  • 项目类别:
Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines
由游离醇和 Boc 保护的胺引导的 Pd 催化 C(sp3)-H 官能化
  • 批准号:
    10606508
  • 财政年份:
    2022
  • 资助金额:
    $ 27.78万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了