Evaluating novel architectural proteins as therapeutic targets for cohesin dysfunction

评估新型结构蛋白作为粘连蛋白功能障碍的治疗靶点

基本信息

批准号：
10593249
负责人：
Eric F. Joyce
金额：
$ 24.38万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593249
关键词：
3-Dimensional Acute Address Affect Applications Grants Architecture Binding Proteins Biological Assay Biology Bruck-de Lange syndrome CALM1 gene CSPG6 gene Candidate Disease Gene Cell Proliferation Cells Chromatin Chromatin Loop Chromosomes Complex Congenital Heart Defects Data Development Developmental Gene Expression Regulation Disease Distal Effectiveness Enhancers Enzymes Fluorescent in Situ Hybridization Functional disorder Future GLI gene Gene Expression Genes Genetic Transcription Genome Genomics Goals HDAC8 gene Heterozygote Human Human Cell Line Image Immunologic Deficiency Syndromes Intellectual functioning disability Knowledge Length Maintenance Measures Mediating Modeling Molecular Mutation Neuraxis Nuclear Organ Patients Pharmaceutical Preparations Phenotype Play Proteins RNA Interference Reagent Role Sampling Symptoms Syndrome Technology Testing Therapeutic Time Translating Validation Work base body system cell growth cohesin craniofacial developmental disease drug candidate experimental study genetic regulatory protein genomic locus insight loss of function mutation novel programs therapeutic development therapeutic target transcriptome transcriptomics

项目摘要

Abstract Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS is primarily caused by mutations in regulatory or structural components of the cohesin complex, which are essential Structural Maintenance of Chromosomes (SMC) protein-containing complexes that interact with chromatin and modulate genome folding. It is hypothesized that CdLS symptoms are a consequence of transcriptional dysregulation due to changes in genome architecture upon cohesin disruption. To date, there are no therapies aimed at correcting cohesin dysfunction or chromatin misfolding directly. These issues are due, in part, to the paucity of factors known to regulate cohesin-mediated chromatin folding. We performed a high-throughput fluorescent in situ hybridization (Hi-FISH)-based screen in human cells, which uses Oligopaint probe technology to detect and measure chromatin interactions in a large number of samples. We targeted ~8,000 human genes, which represent the “druggable genome” and isolated five candidate genes whose depletion can offset cellular phenotypes associated with cohesin dysfunction. The goal of this proposal is to characterize the role of these novel ‘anti-cohesin factors’ in nuclear architecture and cohesin function and test the ability of their inhibition to correct gene misexpression in CdLS models. Through understanding the molecular factors involved in cohesin biology and chromatin folding, we can begin to consider targeted approaches to CdLS therapeutic development.

抽象的 Cornelia de Lange综合征（CDLS）是一种影响多个器官的罕见发育障碍包括中枢神经系统，诱导可变的神经发育延迟。 CDL主要引起通过粘蛋白复合物的调节或结构成分的突变，这是必不可少的结构维持染色体（SMC）蛋白质复合物，与染色质相互作用并调节基因组折叠。假设CDLS符号是转录失调的结果由于基因组结构发生变化，凝聚素破坏。迄今为止，没有针对的疗法直接纠正粘着蛋白功能障碍或染色质错误折叠。这些问题部分是由于缺乏已知来调节粘蛋白介导的染色质折叠的因素。我们在人类细胞中的原位杂交（HI-FISH）屏幕，该屏幕使用寡头探针技术检测并测量大量样品中的染色质相互作用。我们针对约8,000个人类基因代表“可毒基因组”和隔离五个候选基因，其部署可以抵消细胞与粘着蛋白功能障碍相关的表型。该提议的目的是表征这些作用核结构和粘着素功能的新型“抗粘蛋白因子”，并测试其抑制作用的能力在CDLS模型中正确的基因misexpression。通过了解粘蛋白涉及的分子因子生物学和染色质折叠，我们可以开始考虑针对CDLS治疗的目标方法。发展。