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Role for prelamin A in premature and physiological aging

Prelamin A 在过早衰老和生理衰老中的作用

基本信息

批准号：
10672409
负责人：
Susan D. Michaelis
金额：
$ 59.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672409
关键词：
Acceleration Affect Age Aging Animal Model Antibodies Arterial Fatty Streak Atherosclerosis Biological Blood Vessels Bone Development Bone Resorption Bone Tissue C-terminal Cardiovascular Diseases Cell Aging Cells Chronic Chronology Clinical Cultured Cells DNA DNA Sequence Alteration Data Defect Deposition Development Dietary Intervention Disease Dysplasia Event Exhibits Failure to Thrive Fibroblasts Fracture Genetic Genetic Transcription Grant Growth High Fat Diet Human In Vitro Individual Inflammation Inflammatory Response Intervention Lamin Type A Length Life Lipids Longevity Low Density Lipoprotein Receptor Membrane Proteins Metalloproteases Modeling Modification Molecular Mouse Strains Mus Mutation Nuclear Envelope Nuclear Matrix-Associated Proteins Organism Osteoblasts Osteoclasts Osteoporosis Pathology Patients Persons Phenotype Physiological Point Mutation Premature aging syndrome Process Progeria Protein Secretion Proteins Reporting Role Rupture Signal Transduction Site Smooth Muscle Myocytes Stimulator of Interferon Genes Syndrome Testing Tissue Microarray Tissues Variant Vascular Diseases Vascular Smooth Muscle Viral Zinc age related aged bone bone cell bone loss disease phenotype experimental study farnesylation human subject human tissue in vivo insight mouse model normal aging novel prelamin A premature programs response senescence sensor therapeutic target transcriptome transcriptomics

项目摘要

PROJECT SUMMARY This project aims to define the role of farnesylated prelamin A in premature and physiological aging. Genetic mutations leading to defective processing of prelamin A, the precursor for the nuclear scaffold protein lamin A, result in persistence of its farnesyl modification and cause premature aging disorders. The best known of these is Hutchinson-Gilford progeria syndrome (HGPS), in which a truncated farnesylated prelamin A variant called “progerin” is expressed. Mandibuloacral dysplasia-type B (MAD-B) is a related disease, where unprocessed farnesylated prelamin A itself accumulates in cells. Some evidence suggests that prelamin A also accumulates during physiological aging. However, the mechanistic role of farnesylated prelamin A in premature aging disorders remains unclear, and its association with physiological aging has not been rigorously tested. We hypothesize that prelamin A is a driver of osteoporosis and cardiovascular disease that occurs in premature and possibly physiological aging. To specifically examine the consequences of prelamin A accumulation, we generated a novel mouse strain (LmnaL648R/L648R) with a mutation that abolishes its processing by the zinc metalloprotease ZMPSTE24. These mice express solely prelamin A (and no mature lamin A), exhibit profound bone loss, but have a significantly longer lifespan than other progeria models and are thus ideal to study the effects of prelamin A during aging. In Aim 1, we will determine how prelamin A affects the number, function, development, transcriptomes and signaling of bone cells, and compare these to what occurs in physiological aging. We will also assess whether these mice develop vascular disease as they age or develop accelerated atherosclerosis when combined with genetic (Ldlr-/-) and high-fat diet interventions that sensitize mice to atherosclerosis. In Aim 2, we will determine how prelamin A affects cultured cells and define the mechanism(s) by which it promotes cellular alterations related to aging. We will carry out chronological transcriptomic analyses in cultured cells to define the earliest events promoted by prelamin A to distinguish causal changes from chronic responses. We will also test the hypothesis that prelamin A induces nuclear envelope rupture that could stimulate a cytosolic DNA sensor and lead to a transcriptional program of inflammation. We will relate the mechanistic insights obtained from these in vitro experiments to affected cells in the LmnaL648R/L648R mice. In Aim 3, we will determine if prelamin A actually accumulates during physiological aging by examining bone and vascular tissue of young and old mice. We will also probe human tissue arrays and a panel of fibroblasts from young and aged individuals for prelamin A. Elucidating the cellular mechanisms and consequences of prelamin A accumulation could change clinical paradigms for the treatment of prelamin A-based premature aging disorders. More broadly, the results of this project could rigorously implicate prelamin A in physiological aging, identifying it as a potential therapeutic target for age-associated osteoporosis, cardiovascular disease, and possibly other ailments.

项目概要该项目旨在明确法呢基化 prelamin A 在过早衰老和生理衰老中的作用。基因突变导致核支架蛋白前体 prelamin A 的加工缺陷核纤层蛋白 A，导致其法呢基修饰的持续存在并导致过早衰老疾病。最知名的其中包括 Hutchinson-Gilford 早衰综合症 (HGPS)，其中截短的法尼基化 prelamin A 变体被称为“早老素”的表达。 B 型下颌骨发育不良 (MAD-B) 是一种相关疾病，其中未加工的法尼基化前核纤层蛋白 A 本身会在细胞中积累。一些证据表明 prelamin A 也在生理衰老过程中积累。然而，法尼基化前核纤蛋白 A 在过早衰老疾病尚不清楚，其与生理衰老的关系尚未明确经过严格测试。我们假设 prelamin A 是骨质疏松症和心血管疾病的驱动因素因过早衰老和可能的生理衰老而发生的疾病。为了具体检查前核纤层蛋白 A 积累的后果，我们产生了一种新的小鼠品系 (LmnaL648R/L648R)，其具有突变消除了锌金属蛋白酶 ZMPSTE24 对其的加工。这些小鼠仅表达前核纤层蛋白 A（没有成熟的核纤层蛋白 A）表现出严重的骨质流失，但寿命明显长于其它早衰症模型，因此非常适合研究 prelamin A 在衰老过程中的影响。在目标 1 中，我们将确定 prelamin A 如何影响骨的数量、功能、发育、转录组和信号传导细胞，并将它们与生理衰老中发生的情况进行比较。我们还将评估这些小鼠是否随着年龄的增长，会出现血管疾病，或者与遗传因素相结合，会加速动脉粥样硬化 (Ldlr-/-) 和高脂肪饮食干预使小鼠对动脉粥样硬化敏感。在目标 2 中，我们将确定如何 prelamin A 影响培养细胞并确定其促进相关细胞改变的机制到老化。我们将在培养细胞中进行按时间顺序的转录组分析，以确定最早的事件由 prelamin A 促进，以区分因果变化和慢性反应。我们还将检验假设 prelamin A 诱导核膜破裂，从而刺激细胞质 DNA 传感器并导致炎症的转录程序。我们将从这些体外实验中获得的机制见解联系起来对 LmnaL648R/L648R 小鼠中受影响的细胞进行实验。在目标 3 中，我们将确定 prelamin A 是否实际上通过检查年轻和年老小鼠的骨骼和血管组织，在生理衰老过程中积累。我们将还探测人体组织阵列和一组来自年轻人和老年人的成纤维细胞中的前核纤层蛋白 A。阐明 prelamin A 积累的细胞机制和后果可能会改变临床治疗基于 prelamin A 的过早衰老疾病的范例。更广泛地说，这一结果该项目可以严格证明 prelamin A 与生理衰老有关，并将其确定为一种潜在的治疗方法与年龄相关的骨质疏松症、心血管疾病和可能的其他疾病的目标。