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

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

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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.

项目摘要该提议的目的是用脑白血病定义视网膜血管病的机制（RVCL），一种与脑萎缩，失明和过早死亡有关的成人发作的血管痴呆，通常在疾病发作的5 - 10年之内。 RVCL是一种常染色体显性疾病，对治疗难治性通过免疫抑制，尽管RVCL患者会产生自身抗体。引起RVCL的突变在TREX1基因中导致疾病具有100％的渗透率。目前，对此没有有效的治疗毁灭性疾病及其疾病发病机理的机制尚未定义。乔纳森矿工（PI）博士指导宾夕法尼亚大学和坐标的RVCL研究中心照顾来自美国和世界各地的RVCL患者。 Miner博士还领导RVCL- 专注的临床医生和研究人员。矿工实验室最初产生了许多老鼠， RVCL的人类细胞模型，并发现了可能正在驱动的新型分子机制内皮病，细胞衰老和由此产生的血管痴呆。共同研究员是努里博士 Neamati，密歇根大学的医学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器。这种伙伴关系导致了新型动物模型，单细胞RNA-seq研究， TREX1的第一类抑制剂，以及我们发现由RVCL引起的TREX1突变导致复制性衰老和内源性追溯元素失调的失败。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，恢复元素和病理（目标1），使用动物模型来定义TREX1突变体和DNA的功能损害修复途径（AIM 2），并确定使用TREX1 DNase活性的作用酶已导致的TREX1突变小鼠和第一类Trex1抑制剂和蛋白质降解器（AIM 3）。我们的机械研究将广泛阐明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引起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以阐明TREX1和内源性逆转录病毒在细胞中的作用衰老，最终导致了这种单基因血管性痴呆的新疗法。