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Novel mechanism of HSF1-mediated neuroprotection

HSF1介导的神经保护新机制

基本信息

批准号：
9282474
负责人：
Santosh R D'Mello
金额：
$ 18.26万
依托单位：
SOUTHERN METHODIST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

项目摘要

SUMMARY Enhanced activity of the heat shock factor-1 (HSF1) transcription factor has protective effects in a variety of tissue culture and in vivo models of protein aggregation-associated neurodegenerative disease. This neuroprotective effect of HSF1 is thought to be mediated through a stimulation of transcription of genes encoding heat shock proteins (HSPs). By acting as molecular chaperones the newly produced HSPs re-fold or help degrade misfolded proteins in cells that suffer thermal or proteotoxic stress. Stimulation of HSP gene transcription by HSF1 requires its homo-trimerization and binding to sequences called heat shock elements (HSEs) located mostly in the promoters of HSP genes. We recently demonstrated that HSF1 can protect neurons from both proteotoxic and non-proteotoxic death by a mechanism does not require its trimerization and is HSP-independent. The goal of this this proposal is to understand this novel HSP-independent mechanism of neuroprotection. We propose that HSF1 acts by binding to non-HSE sequences as a monomer and regulating genes unconnected to HSPs and other chaperones. We propose that neuroprotection by HSF1 through this non-canonical mechanism requires the activity of histone deacetylases (HDACs) and interaction with the Class III HDAC, SIRT1. The specific aims of our project are: The specific aims of our project are - Aim 1: To understand the role of histone deacetylases in HSF1-mediated neuroprotection. Aim 2: To identify genomic sequences bound by monomeric HSF1 using two separate approaches – ChiP- Seq and Bind-N-Seq. Aim 3: To identify genes regulated by monomeric HSF1 using RNA-Seq. Understanding the mechanism will lead to a better understanding of the process of neurodegeneration and provide the basis for the development of novel therapeutic approaches for neurodegenerative diseases.

总结热休克因子-1（HSF 1）转录因子活性增强具有保护作用各种组织培养和体内模型的蛋白质聚集相关的神经退行性疾病HSF 1的这种神经保护作用被认为是通过通过刺激编码热休克蛋白（HSP）的基因的转录。通过作用作为分子伴侣，新产生的HSP重新折叠或帮助降解错误折叠的蛋白质，受到热或蛋白毒性应激的细胞。热休克因子1对热休克蛋白基因转录的促进作用需要它的同源三聚体和结合序列称为热休克元件（HSEs）主要位于HSP基因的启动子区。我们最近证明了HSF 1可以保护神经元因蛋白毒性和非蛋白毒性死亡的机制并不需要其三聚化并且是HSP非依赖性的。这个提案的目的是为了理解这部小说 HSP非依赖性神经保护机制。我们认为HSF 1通过与作为单体的非HSE序列和与HSPs和其他不连接的调节基因监护人我们认为HSF 1通过这种非经典机制的神经保护作用需要组蛋白脱乙酰酶（HDAC）的活性和与III类HDAC的相互作用， SIRT 1.我们项目的具体目标是：我们项目的具体目标是-目标1：了解组蛋白去乙酰化酶在HSF 1介导的神经保护中的作用。目标2：使用两种不同的方法- ChiP- Seq和Bind-N-Seq。目的3：利用RNA-Seq技术鉴定单体HSF 1调控的基因。了解这一机制将有助于更好地理解并为开发新的治疗方法提供基础治疗神经退行性疾病