Molecular Basis of Coats Plus Disease

Coats Plus 疾病的分子基础

基本信息

批准号：
10607126
负责人：
Weihang Chai
金额：
$ 39.09万
依托单位：
LOYOLA UNIVERSITY CHICAGO
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：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607126
关键词：
Acceleration Affect Aging Bilateral Binding Binding Proteins Biochemical Biological Assay Biophysics Blood Vessels Brain Calcium Calcium Signaling Cells Chromosome Breakage Coats&apos disease Complex Cytoprotection DNA DNA biosynthesis DNA replication fork Data Defect Development Disease Ensure Enzymes Event Exhibits Eye Failure Functional disorder Gastrointestinal tract structure Genes Genetic Diseases Genome Genome Stability Genomic Instability Goals Growth Human Investigation Knowledge Life Maintenance Malignant Neoplasms Mediating Microcephaly Molecular Mutation Neurodevelopmental Disorder Organ Pathological Dilatation Pathology Pathway interactions Phospho-Specific Antibodies Phosphoproteins Phosphorylation Predisposition Proteins Reagent Research Retina Role SS DNA BP Signal Pathway Signal Transduction Single-Stranded DNA Site Stress Response Signaling Syndrome System Technology Telangiectasis Testing Up-Regulation Work biological adaptation to stress bone calcification combat design developmental disease gastrointestinal genome integrity insight loss of function mutation multidisciplinary novel nuclease pathological aging phosphoproteomics preservation prevent protein function rare genetic disorder recruit replication stress response single molecule targeted treatment therapeutically effective

项目摘要

The Coats plus syndrome is a rare and life-threatening genetic disorder characterized by multi-system developmental defects that lead to bilateral exudative retinopathy, retinal telangiectasias, growth retardation, intracranial calcifications, bone abnormalities, gastrointestinal vascular ectasias, and common early-aging pathological features. Like many other developmental disorders, Coats plus is caused by defects in genes involved in maintaining global genome integrity. Specifically, it is caused by loss-of-function mutations in the human CTC1/STN1/TEN1 (CST) complex, which is a trimeric complex that preferentially binds to G-rich ssDNA or ss-ds DNA junctions and is critical for preventing genome instabilities arising from replication perturbation. We hope to aid in better understanding of disease development and designing of effective therapeutic strategies by investigating the mechanisms governing genome stability under replication stress. In response to fork stalling, signaling cascades activate multiple pathways including fork reversal, translesion synthesis, repriming downstream of stalled sites, and dormant origin firing to rescue stalled replication. Activities of these pathways need to be tightly regulated to ensure replication fidelity. The objectives of this proposal is to delineate a novel signaling pathway in response to replication stress, elucidate how it regulates protein interplays and recruitment at stalled forks, and understand the mechanism regulating the repriming pathway. In Aim 1, we hypothesize that a calcium-dependent signaling pathway phosphorylates STN1 to activate CST at stalled forks to protect the stability of stalled forks. We will elucidate this new signaling pathway and determine how this pathway antagonizes unscheduled nascent strand DNA degradation and regulates fork protection. In Aim 2, we will investigate how this signaling pathway regulates the interplay of single-strand DNA binding proteins at forks and other fork binding proteins. In Aim 3, we will investigate the mechanism for restricting excessive repriming to prevent ssDNA gap formation and genome instability. We will combine highly sensitive cell-based analyses, single-molecule and powerful biochemical assays to accomplish the goals of the proposed research. We expect that our efforts will identify new factors and pathways regulating the rescue of stalled replication and the preservation of genome stability.

大衣加综合征是一种罕见且威胁生命的遗传疾病，其特征是多系统发育缺陷导致双侧渗出性视网膜病，视网膜毛细血管扩张，生长迟钝，颅内钙化，骨异常，胃肠道血管临界和常见的早期衰老病理特征。像许多其他发育障碍一样，大衣加也是由基因缺陷引起的参与维持全球基因组完整性。具体而言，它是由功能丧失突变引起的人CTC1/STN1/TEN1（CST）配合物，它是一种三聚体配合物，优先结合G-富含G的ssDNA 或SS-DS DNA连接，对于预防复制扰动引起的基因组不稳定性至关重要。我们希望通过研究在复制应力下控制基因组稳定性的机制。为了响应叉子拖延，信号传导级联激活多种途径，包括叉反转，translesion合成，谴责停滞地点的下游和休眠的起源射击以挽救停滞的复制。这些途径的活动需要严格调节以确保复制保真度。该提议的目标是描绘一本小说响应复制应力的信号通路，阐明其如何调节蛋白质相互作用和募集在失速的叉子上，了解调节谴责途径的机制。在AIM 1中，我们假设依赖钙的信号通路磷酸化STN1在失速叉处激活CST以保护失速叉的稳定性。我们将阐明这种新的信号通路，并确定该途径如何拮抗外生的新生链DNA降解并调节叉子保护。在AIM 2中，我们将研究该信号通路如何调节分叉和其他叉子结合蛋白。在AIM 3中，我们将调查限制过度谴责的机制预防ssDNA间隙形成和基因组不稳定性。我们将结合高度敏感的基于细胞的分析，单分子和强大的生化测定法以实现拟议研究的目标。我们期望我们的努力将确定规范停滞复制的新因素和途径保存基因组稳定性。