Role of TREX1 in age-related hereditary leukoencephalopathy

TREX1 在年龄相关遗传性白质脑病中的作用

基本信息

批准号：
10803373
负责人：
Jonathan J Miner
金额：
$ 79.14万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10803373
关键词：
Adult Affect Age Aging Animal Model Autoantibodies Autoimmunity Automobile Driving B-Lymphocytes Blindness Blood Vessels Brain Diseases C-terminal Cause of Death Cell Aging Cell Death Cell Nucleus Cell model Cells Cerebral small vessel disease Cerebrum Cessation of life Chromatin Structure Chronic Cytosol DNA DNA Damage DNA Repair DNA Sequence Dementia Deoxyribonucleases Disease Endogenous Retroviruses Endoplasmic Reticulum Enzymes Euchromatin Failure Family Frameshift Mutation Genome Genomic DNA Goals Heterochromatin Heterozygote Human Human Genome Humoral Immunities Immune Immunosuppression Individual Inherited Interferons Knock-out Laboratories Lead Lesion Leukoencephalopathy Mammalian Cell Mediating Medicine Michigan Microvascular Dysfunction Modeling Molecular Mus Mutant Strains Mice Mutation Onset of illness Organ Pathogenesis Pathology Pathway interactions Patients Penetrance Pennsylvania Phenotype Poly(ADP-ribose) Polymerase Inhibitor Population Predisposition Premature aging syndrome Production Proteins Refractory Research Research Personnel Retina Retroelements Retroviridae Role Sampling Serology Stimulator of Interferon Genes TREX1 gene TREX1 protein Testing Transgenic Mice United States Universities Vascular Dementia Vascular Diseases Viral Work age related autosome care coordination cell type cerebral atrophy chromatin remodeling disability effective therapy enzyme activity human disease inhibitor innovation insight mammalian genome mouse model mutant novel novel therapeutics premature prevent response restraint senescence single-cell RNA sequencing viral DNA white matter

项目摘要

Project Abstract The goal of this proposal is to define the mechanisms of retinal vasculopathy with cerebral leukoencephalopathy (RVCL), an adult-onset vascular dementia associated with brain atrophy, blindness, and premature death, usually within 5-10 years of disease onset. RVCL is an autosomal dominant disease that is refractory to treatment with immunosuppression despite the fact that RVCL patients develop autoantibodies. RVCL-causing mutations in the TREX1 gene cause disease with 100% penetrance. Currently, there is no effective treatment for this devastating disease, and the mechanisms of disease pathogenesis have not yet been defined. Dr. Jonathan Miner (PI) directs the RVCL Research Center at the University of Pennsylvania and coordinates care of RVCL patients from around the United States and the world. Dr. Miner also leads a team of RVCL- focused clinicians and investigators. Preliminarily the Miner laboratory has generated numerous mouse and human cellular models of RVCL and discovered novel molecular mechanisms that may be driving endotheliopathy, cellular senescence, and the resulting vascular dementia. The co-investigator is Dr. Nouri Neamati, a medicinal chemist and biochemist at the University of Michigan. Dr. Neamati is developing TREX1 inhibitors and protein degraders. This partnership has led to novel animal models, single-cell RNA-seq studies, and first-in-class inhibitors of TREX1, as well as our discovery that RVCL-causing TREX1 mutations lead to failure of replicative senescence and dysregulation of endogenous retroelements. Here, we propose to use cellular and animal models to define the role of TREX1 in regulating DNA damage, retroelements, and pathology (Aim 1), to use animal models to define functions of TREX1 mutants and a DNA damage repair pathway in humoral immunity (Aim 2), and to determine the role of TREX1 DNase activity using an enzyme-dead TREX1 mutant mice and first-in-class TREX1 inhibitors and protein degraders (Aim 3). Our mechanistic studies will broadly elucidate functions of TREX1 and the role of TREX1-mediated DNA damage in a mouse model expressing TREX1 mutants known to cause small vessel disease and vascular dementia in humans. Insights gained from our work may clarify the role of TREX1 and endogenous retroviruses in cellular senescence, eventually leading to new therapies for this monogenic vascular dementia.

项目摘要该提案的目标是确定视网膜血管病变合并脑白质脑病的机制（RVCL），一种成人发病的血管性痴呆，与脑萎缩、失明和过早死亡相关，通常在发病后 5-10 年内发生。 RVCL 是一种难以治疗的常染色体显性遗传疾病尽管 RVCL 患者会产生自身抗体，但仍需进行免疫抑制。 RVCL 引起的突变 TREX1 基因导致疾病的外显率达 100%。目前对此尚无有效治疗方法毁灭性的疾病，其发病机制尚未明确。 Jonathan Miner 博士（PI）领导宾夕法尼亚大学 RVCL 研究中心并负责协调护理来自美国和世界各地的 RVCL 患者。 Miner 博士还领导着 RVCL 团队- 专注于临床医生和研究人员。迈纳实验室初步培育出大量小鼠和 RVCL 的人类细胞模型并发现了可能驱动的新分子机制内皮病、细胞衰老以及由此产生的血管性痴呆。共同研究员是 Nouri 博士 Neamati，密歇根大学药物化学家和生物化学家。 Neamati 博士正在开发 TREX1 抑制剂和蛋白质降解剂。这种伙伴关系带来了新的动物模型、单细胞 RNA 测序研究、和 TREX1 的一流抑制剂，以及我们发现引起 RVCL 的 TREX1 突变导致复制衰老失败和内源性逆转录因子失调。在这里，我们建议使用细胞和动物模型来定义TREX1在调节DNA损伤中的作用，逆转录元件和病理学（目标 1），使用动物模型来定义 TREX1 突变体和 DNA 的功能体液免疫中的损伤修复途径（目标 2），并使用 TREX1 DNase 活性确定 TREX1 DNase 活性的作用酶死亡的 TREX1 突变小鼠和一流的 TREX1 抑制剂和蛋白质降解剂（目标 3）。我们的机制研究将广泛阐明 TREX1 的功能以及 TREX1 介导的 DNA 损伤在表达TREX1突变体的小鼠模型已知会导致小血管疾病和血管性痴呆人类。从我们的工作中获得的见解可能会阐明 TREX1 和内源性逆转录病毒在细胞中的作用衰老，最终导致这种单基因血管性痴呆的新疗法。