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Epigenetic Pathology and Therapy in Huntington's Disease

亨廷顿病的表观遗传学病理学和治疗

基本信息

批准号：
10630937
负责人：
Ernest Fraenkel
金额：
$ 40.85万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630937
关键词：
Acceleration Affect Age Age of Onset Alleles Animal Model BETA2 protein Biological Assay Biological Models Brain Brain region Cell Culture Techniques Cell Differentiation process Cell Nucleus Cell model Cells Chromatin Corpus striatum structure Data Disease Disease model ELK1 gene Energy Metabolism Epigenetic Process Genes Genetic Genetic Transcription Genomics Goals Grant Human Huntington Disease Huntington gene In Vitro Individual Inherited Intervention Investigation Link Lipid Biochemistry Lipids Literature Measures Methods Modeling Molecular Multiomic Data Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Impairment Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phosphotransferases Pluripotent Stem Cells Population Prostaglandin D2 Proteins Proteomics Research Resolution Signal Transduction Symptoms System Systems Biology Technology Testing Therapeutic Therapeutic Intervention Transcript Variant Work cell type data integration disease-causing mutation effective therapy epigenome epigenomics gene therapy genetic variant group intervention improved in vivo induced pluripotent stem cell innovation insight metabolomics mutant nervous system disorder novel strategies novel therapeutic intervention programs response stem cell model therapeutically effective transcriptome sequencing

项目摘要

The simple genetic cause of Huntington’s disease contrasts starkly with the vast number of pathways that are affected by the mutation. Some of these pathway-level changes may persist even if the mutated allele of the disease-causing gene (HTT) can be corrected through gene therapy or related methods. During the first granting period, our analysis of HD models identified several potential therapeutic directions, including ones closely tied to epigenetics (the transcriptional regulators NEUROD1, WNTand ELK-1), as well as pathways that interact with epigenomic changes (energy metabolism and lipid biochemistry). Some of these effects were restricted to particular cell types in the brain. We also found evidence that mutant HTT (mHTT) expression causes neurodevelopmental impairments, changing the distribution of cell types in the brain. We and others have also identified a significant number of genetic variants in the human population for which there is significant support for an impact of that variant on HD age of onset (AOO). In the current proposal, we examine the therapeutic potential of interventions based on these findings. We will target these pathways in mice, measuring how interventions alter transcription, the epigenome, signaling and metabolomics. A critical innovation is our use of single-cell and spatially resolved methods to examine how responses to mHTT and therapeutics vary among different types of cells. Equally important, we will differentiate specific cell types from induced-pluripotent stem cells (iPSC) in vitro to examine cell-type specific effects in human cells. Using an approach based in systems biology we will look for common pathways that are affected by the genetic AOO modifiers, the candidates from our prior grant period and leads from the literature. Our approach is highly innovative, as it uses cutting edge experimental methods with single-cell and spatial resolution to reveal aspects of HD that cannot be detected in homogenates. We also computationally integrate multi-omic data (genomics, epigenomics, transcripts, proteins and metabolites) from the individual cells and brain regions to uncover therapeutic pathways. The research is highly significant, as it seeks to guide therapeutic discovery for an invariably fatal neurodegenerative disease. We expect that the impact of our work will extend beyond HD, by providing a model for how to measure and model cell-type specific neurodegeneration to identify therapeutic approaches.

亨廷顿氏病的简单遗传原因与亨廷顿氏病的大量遗传途径形成鲜明对比。受到突变的影响。这些途径水平的变化中的一些可能持续存在，即使突变的等位基因的突变，致病基因（HTT）可以通过基因治疗或相关方法来纠正。在第一次授予在此期间，我们对HD模型的分析确定了几个潜在的治疗方向，表观遗传学（转录调节因子NEUROD 1，WNT和ELK-1），以及与表观基因组变化（能量代谢和脂质生物化学）。其中一些影响仅限于大脑中的特定细胞类型。我们还发现了突变HTT（mHTT）表达导致神经发育障碍，改变大脑中细胞类型的分布。我们和其他人也在人群中发现了大量的遗传变异，该变异对HD发病年龄（AOO）的影响。在目前的建议中，我们研究了基于这些发现的干预措施的治疗潜力。我们将在小鼠中靶向这些途径，测量干预如何改变转录，表观基因组，信号传导和代谢组学一个关键的创新是我们使用单细胞和空间分辨的方法来研究如何对mHTT和治疗剂的反应在不同类型的细胞中不同。同样重要的是，体外诱导多能干细胞（iPSC）的特定细胞类型，以检查细胞类型特异性作用，人体细胞使用基于系统生物学的方法，我们将寻找受影响的共同途径通过遗传AOO修饰剂，从我们以前的资助期和领导的文献候选人。我们这种方法是高度创新的，因为它使用了具有单细胞和空间分辨率的尖端实验方法以揭示不能在匀浆中检测到的HD方面。我们还计算整合多组学来自单个细胞和大脑区域的数据（基因组学、表观基因组学、转录物、蛋白质和代谢物）来揭示治疗途径这项研究非常重要，因为它试图指导治疗发现一种致命的神经退行性疾病我们希望我们的工作的影响将超越HD，通过提供如何测量和模拟细胞类型特异性神经变性的模型，接近。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements.

DOI：
10.1038/s41467-017-00353-6
发表时间：
2017-09-20
期刊：
Nature communications
影响因子：
16.6
作者：
Pirhaji L;Milani P;Dalin S;Wassie BT;Dunn DE;Fenster RJ;Avila-Pacheco J;Greengard P;Clish CB;Heiman M;Lo DC;Fraenkel E
通讯作者：
Fraenkel E

Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.

DOI：
10.1016/j.cels.2016.12.011
发表时间：
2017-02-22
期刊：
Cell systems
影响因子：
9.3
作者：
Khurana V;Peng J;Chung CY;Auluck PK;Fanning S;Tardiff DF;Bartels T;Koeva M;Eichhorn SW;Benyamini H;Lou Y;Nutter-Upham A;Baru V;Freyzon Y;Tuncbag N;Costanzo M;San Luis BJ;Schöndorf DC;Barrasa MI;Ehsani S;Sanjana N;Zhong Q;Gasser T;Bartel DP;Vidal M;Deleidi M;Boone C;Fraenkel E;Berger B;Lindquist S
通讯作者：
Lindquist S

Phenotyping Neurodegeneration in Human iPSCs.

DOI：
10.1146/annurev-biodatasci-092820-025214
发表时间：
2021-07-20
期刊：
Annual review of biomedical data science
影响因子：
0
作者：
通讯作者：

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet.

DOI：
10.1016/j.celrep.2017.11.059
发表时间：
2017-12-12
期刊：
Cell reports
影响因子：
8.8
作者：
Soltis AR;Kennedy NJ;Xin X;Zhou F;Ficarro SB;Yap YS;Matthews BJ;Lauffenburger DA;White FM;Marto JA;Davis RJ;Fraenkel E
通讯作者：
Fraenkel E

Shallow Sparsely-Connected Autoencoders for Gene Set Projection.

用于基因集投影的浅层稀疏连接自动编码器。