Synthetic chromatin for cancer research

用于癌症研究的合成染色质

• 批准号: 8768323
• 负责人: Karmella Ann Haynes
• 金额: $ 15.71万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768323
• 关键词: Address; Affect; Applications Grants; Arizona; Binding; Biological; Biological Models; Cancer Intervention; Cancer Remission; Cell Proliferation; Cells; Chimeric Proteins; Chromatin; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Computational Biology; DNA; Data; Development; Drug Targeting; Emerging Technologies; Engineering; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epigenetic Process; Faculty; Frequencies; Funding; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic Code; Genetic Materials; Genetic Transcription; Goals; Health system; Heterogeneity; Histones; Human; Institutes; K-Series Research Career Programs; Kidney; Luciferases; Malignant Neoplasms; Marketing; Mediating; Medicine; Mentored Research Scientist Development Award; Mentors; Methodology; Methods; Modeling; Molecular Biology; Molecular Conformation; Nonlinear Dynamics; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Piper; Population; Problem Solving; Protein Binding; Proteins; Reporter Genes; Repressor Proteins; Research; Research Personnel; Research Proposals; Resistance; Risk; Schools; Scientist; Silver; Systems Biology; Testing; Time; Tissues; Transcription Coactivator; Translational Research; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States National Institutes of Health; Universities; Virginia; Work; anticancer research; base; biological systems; cancer cell; cancer therapy; career; chemotherapy; chromatin protein; cohort; design; drug market; fighting; improved; in vivo; inhibitor/antagonist; innovation; mathematical model; medical schools; member; new technology; novel; post-doctoral training; professor; prognostic; programs; protein structure; public health relevance; research study; small molecule; synthetic biology; synthetic construct; synthetic protein; theories; therapeutic gene; transcription factor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): This is an application for a K01 award for Dr. Karmella Haynes, an assistant professor in the Ira A. Fulton School of Biological and Health Systems Engineering (SBHSE) at Arizona State University (ASU). Dr. Haynes is establishing herself as a young investigator in. This K01 award will provide Dr. Haynes with the protected time and support necessary to accomplish the following goals: (1) to become an expert in computational biology methods, (2) to become engaged in translational research collaborations with clinical scientists at the Mayo Clinic in Phoenix, AZ and Rochester, MN, and (3) to develop an independent research career. To achieve these goals, Dr. Haynes has assembled a mentoring team comprised of a principal mentor, Dr. Mark Spano, Research Professor in the SBHSE who is an expert in experimental nonlinear dynamics and complexity theory as applied to biological systems, and two co- mentors: Dr. Joshua LaBaer, a Professor and the Director of the Virginia G. Piper Center for Personalized Medicine (CPD) at the Biodesign Institute at ASU; and Dr. Pamela Silver, a Professor in the Department of Systems Biology and founding core faculty member at the Wyss Institute of Biologically Inspired Design at Harvard Medical School. The misregulation of chromatin, the central DNA-protein structures that package genetic material within human cells, is a well-recognized factor of oncogenesis and poor prognostic outcome. Dr. Haynes' research will focus on using a model system to develop and test synthetic chromatin proteins that interfere with the methyl-histone cancer-associated epigenetic signature (Aim 1), solving the problem of regulating cell-to-cell heterogeneity in the expression of chromatin-regulated genes (Aim 2), and reactivating chromatin-repressed tumor-suppressor genes with synthetic chromatin proteins (Aim 3). In Aim 1, Dr. Haynes will expand upon her research background in chromatin and synthetic biology to construct and quantitatively assess the activity of the synthetic proteins. In Aim 2, Dr. Haynes will work closely with Dr. Spano to computationally model and verify threshold protein concentrations at which cell phenotypes become uniform across a large population. In Aim 3, Dr. Haynes will work with Dr. LaBaer to complete transcription-profiling experiments in synthetic protein- treated cancer cells. The experiments will generate preliminary data that will form the basis of a methodology to use modular peptide motifs to build synthetic chromatin proteins that activate dormant therapeutic genes in a predictable, reliable manner. A study that applies this methodology to halt cancer progression in vivo without undesired pleiotropic effects will be proposed in an R01 grant application before the end of the K award.

描述（由申请人提供）：这是一份K01奖的申请，申请对象是亚利桑那州立大学（ASU） Ira a . Fulton生物与健康系统工程学院（shbhse）的助理教授Karmella Haynes博士。海恩斯博士正在成为一名年轻的调查员。该K01奖将为Haynes博士提供必要的保护时间和支持，以实现以下目标：(1)成为计算生物学方法方面的专家，(2)与位于亚利桑那州凤凰城和罗切斯特的梅奥诊所的临床科学家进行转化研究合作，以及(3)发展独立的研究事业。为了实现这些目标，Haynes博士组建了一个指导团队，其中包括一位主要导师，shbhse研究教授Mark Spano博士，他是实验非线性动力学和复杂性理论应用于生物系统的专家，以及两位共同导师：Joshua LaBaer博士，亚利桑那州立大学生物设计研究所弗吉尼亚G. Piper个性化医学中心（CPD）的教授和主任；以及Pamela Silver博士，她是哈佛医学院系统生物系教授，也是Wyss生物启发设计研究所的创始核心教员。染色质是人类细胞内包装遗传物质的核心dna -蛋白质结构，其调控不当是公认的肿瘤发生和预后不良的因素。Haynes博士的研究将集中在使用模型系统来开发和测试干扰甲基组蛋白癌症相关表观遗传特征的合成染色质蛋白（Aim 1），解决染色质调节基因表达的细胞间异质性问题（Aim 2），以及用合成染色质蛋白重新激活染色质抑制的肿瘤抑制基因（Aim 3）。在Aim 1中，Haynes博士将扩展她在染色质和合成生物学方面的研究背景，以构建和定量评估合成蛋白的活性。在目标2中，Haynes博士将与Spano博士密切合作，计算模型并验证阈值蛋白浓度，在该阈值蛋白浓度下，细胞表型在大量人群中变得一致。在Aim 3中，Haynes博士将与LaBaer博士合作完成合成蛋白处理癌细胞的转录谱实验。实验将产生初步数据，这些数据将形成一种方法的基础，该方法使用模块化肽基序构建合成染色质蛋白，以可预测、可靠的方式激活休眠的治疗基因。在K奖结束前，将在R01拨款申请中提出一项应用该方法在体内停止癌症进展而不产生不良多效效应的研究。