Aptamer probes for Epigenetic Peptide Targets

描述(由申请人提供)： 表观遗传异常是许多人类疾病的基础，这些疾病缺乏明显的基因变化。例如，双相情感障碍和精神分裂症等精神健康疾病与代谢神经递质的酶的启动子的表观遗传变化有关。表观遗传因素已被证明在其他疾病中发挥作用，包括癌症、自闭症、哮喘和生殖疾病。老化的同卵双胞胎的基因表达差异表明，表观遗传漂移可能与随着年龄增长而出现的慢性疾病有关。表观基因组研究最有希望的方面之一是，与遗传异常不同，表观遗传异常可能是可逆的，通过调节稳定或重塑特定染色质状态的酶的活性。在这个项目中，将使用OrthoSystems新的和非常成功的方法--高通量适体筛选(HTSA)，从核酸文库中筛选一组表观遗传肽和蛋白质靶标，以发现具有高亲和力和特异性的结合蛋白质的DNA/RNA分子。HTSA适配子HITS将在标准实验条件下进行灵敏度、交叉反应性和稳健性研究。在第二阶段，达到或超过我们性能标准的适配子将通过NIH试剂库(限量提供)提供给研究社区，或从OrthoSystems，Inc.付费获得(带附件化学的完整产品线)。这些适体产物将作为低成本、可再生、标准化的亲和试剂用于表观基因组研究。这一合作项目将由OrthoSystems，Inc.牵头，并与锡拉丘兹大学签订分包合同。 公共卫生相关性： 表观遗传异常是精神健康疾病(如双相情感障碍和精神分裂症)发病机制的基础，它导致产生代谢神经递质分子的酶的基因调节发生变化。表观遗传因素在其中发挥作用的其他疾病包括癌症、自闭症、哮喘和生殖疾病，也可能与随着年龄增长而出现的慢性病有关。众所周知，许多蛋白质在DNA紧密堆积在染色体中或可用于基因表达的方式中起着关键作用。该项目将提供新的、更有效的工具来测量这些蛋白质被修饰的程度。与遗传异常不同，表观遗传变化可能是可逆的，它通过调节酶的活性来稳定或重塑DNA在染色体中的堆积。

DESCRIPTION (provided by applicant): Epigenetic aberrations underlie the pathogenesis of a number of human diseases that lack clear genetic alterations. For example, mental health diseases such as bipolar disorder and schizophrenia are associated with epigenetic changes in the promoters of enzymes that metabolize neurotransmitters. Other diseases in which epigenetic factors have been shown to play a role include cancer, autism, asthma and reproductive diseases. Gene expression differences in aging monozygotic twins suggest that epigenetic drift may be associated with chronic diseases that appear as we age. One of the most promising aspects of epigenomic research is that, unlike genetic aberrations, epigenetic aberrations are potentially reversible, by modulating the activities of the enzymes that stabilize or remodel specific chromatin states. In this project a set of epigenetic peptide and protein targets will be screened against libraries of nucleic acids using OrthoSystems new and highly successful approach, High Throughput Screening of Aptamers (HTSA), for discovery of DNA/RNA molecules that bind proteins with high affinity and specificity. HTSA aptamer hits will be investigated under standard experimental conditions for sensitivity, cross reactivity and robustness. In Phase II, aptamers that meet or exceed our performance standards will be made available to the re- search community through NIH reagent repositories (limited offering) or for a fee from OrthoSystems, Inc (full product line with attachment chemistry.) These aptamer products will serve as low cost, renewable, standar- dized affinity reagents for epigenomic research. This collaborative project will be led by OrthoSystems, Inc. with a subcontract to Syracuse University. PUBLIC HEALTH RELEVANCE: Epigenetic aberrations underlie the pathogenesis of mental health diseases, such as bipolar disorder and schizophrenia, by causing changes in the regulation of genes that produce enzymes to metabolize neuro transmitter molecules. Other diseases in which epigenetic factors play a role include cancer, autism, asthma and reproductive diseases, and may also be associated with chronic diseases that appear as we age. Many proteins are known to have critical roles in the manner in which DNA is packed tightly into chromo- somes or is available for expression of genes. This project will provide new and far more effective tools to measure the degree to which these proteins are modified. Unlike genetic aberrations, epigenetic changes are potentially reversible by modulating the activities of the enzymes that stabilize or remodel the packing of DNA in chromosomes.