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

• 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
• 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

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 本研究的目的是明确视网膜血管病变合并脑白质脑病的发病机制 （RVCL），一种与脑萎缩、失明和过早死亡相关的成人发作的血管性痴呆， 通常在发病后5-10年内。RVCL是一种常染色体显性遗传疾病，难以治疗 尽管RVCL患者会产生自身抗体，导致RVCL的突变 TREX 1基因的突变导致100%的死亡率。目前，对此尚无有效的治疗方法 毁灭性疾病，疾病的发病机制尚未确定。 博士乔纳森·迈纳（PI）指导宾夕法尼亚大学RVCL研究中心， 来自美国和世界各地的RVCL患者的护理。Miner博士还领导了一个RVCL团队- 专注的临床医生和研究人员。Miner实验室已经培养了大量的小鼠， RVCL的人类细胞模型，并发现了新的分子机制， 内皮病、细胞衰老和由此产生的血管性痴呆。合作研究者是努里博士 Neamati说，他是密歇根大学的药物化学家和生物化学家。Neamati博士正在开发TREX 1 抑制剂和蛋白质降解剂。这种伙伴关系导致了新的动物模型，单细胞RNA-seq研究， 和TREX 1的第一类抑制剂，以及我们发现RVCL引起的TREX 1突变导致 复制性衰老的失败和内源性逆转录因子的失调。 在这里，我们建议使用细胞和动物模型来定义TREX 1在调节DNA损伤中的作用， 逆转录因子和病理学（目的1），使用动物模型来定义TREX 1突变体和DNA的功能。 损伤修复途径在体液免疫（目的2），并确定TREX 1 DNA酶活性的作用， 一个酶死亡TREX 1突变小鼠和一流的TREX 1抑制剂和蛋白质降解剂（目标3）。我们 机制研究将广泛阐明TREX 1的功能和TREX 1介导的DNA损伤在 一种表达TREX 1突变体的小鼠模型，该突变体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澄清TREX 1和内源性逆转录病毒在细胞凋亡中的作用。 衰老，最终导致这种单基因血管性痴呆的新疗法。