Synthetic chromatin for cancer research

描述（由申请人提供）：这是一个K 01奖博士卡梅拉海恩斯，在伊拉A助理教授的申请。亚利桑那州立大学（ASU）的富尔顿生物与健康系统工程学院（SBHSE）。海恩斯博士正在成为一名年轻的调查员。该K 01奖将为Haynes博士提供必要的时间和支持，以实现以下目标：（1）成为计算生物学方法的专家，（2）与亚利桑那州凤凰城和明尼苏达州罗切斯特的马约诊所的临床科学家进行转化研究合作，（3）发展独立的研究生涯。为了实现这些目标，Haynes博士组建了一个指导团队，由主要导师Mark Spano博士和两位共同导师组成：Mark Spano博士是SBHSE的研究教授，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，约书亚LaBaer博士是弗吉尼亚G.亚利桑那州立大学生物设计研究所的Piper个性化医学中心（CPD）;以及系统生物学系教授、哈佛医学院生物启发设计研究所的创始核心教员Pamela银博士。 染色质是人类细胞内包装遗传物质的中心DNA-蛋白质结构，其失调是肿瘤发生和预后不良的公认因素。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），解决调节染色质调节基因表达中细胞间异质性的问题（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）。在目标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质的活性。在目标2中，Haynes博士将与Spano博士密切合作，对细胞表型在大量人群中变得均匀的阈值蛋白质浓度进行计算建模和验证。在目标3中，Haynes博士将与LaBaer博士合作，在合成蛋白质处理的癌细胞中完成转录谱实验。这些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来构建合成染色质蛋白，这些蛋白以可预测的、可靠的方式激活休眠的治疗基因。在K奖结束前，将在R 01资助申请中提出一项应用这种方法在体内阻止癌症进展而没有不希望的多效性效应的研究。

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.