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

• 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
• 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

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.

项目摘要 该项目旨在确定法尼基化的prelamin A在过早和生理衰老中的作用。 基因突变导致核支架蛋白前体层蛋白A加工缺陷 核纤层蛋白A，导致其法尼基修饰持续存在并引起过早衰老病症。最著名的 其中之一是Hutchinson-Gilford早老综合征（HGPS），其中截短的法尼基化前核纤层蛋白A变体 称为“早老蛋白”的蛋白质。下颌骨肢端发育不良B型（MAD-B）是一种相关疾病，其中 未加工的法尼基化的前核纤层蛋白A本身在细胞中积累。一些证据表明，前层蛋白A也 在生理老化过程中积累。然而，法尼基化的前核纤层蛋白A在 过早衰老的疾病仍然不清楚，它与生理衰老的关系还没有得到证实。 严格测试。我们假设层蛋白前体A是骨质疏松症和心血管疾病的驱动因素， 过早或生理性衰老时发生的疾病。专门检查 由于前层蛋白A积累的结果，我们产生了一种新的小鼠品系（LmnaL 648 R/L 648 R）， 突变，该突变消除了锌金属蛋白酶ZMPSTE 24对其的加工。这些老鼠只表达 核纤层蛋白A前体（没有成熟的核纤层蛋白A）表现出严重的骨丢失，但寿命显著长于 其他早老症模型，因此是理想的研究在老化过程中的影响prelamin A。在目标1中，我们 确定前层蛋白A如何影响骨的数量、功能、发育、转录组和信号传导， 细胞，并将其与生理老化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，他们会患上血管疾病，或者当与遗传因素结合时，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 前层蛋白A影响培养的细胞，并确定其促进细胞改变的机制， 变老我们将在培养的细胞中进行按时间顺序的转录组学分析，以确定最早的事件 由前层蛋白A促进，以区分因果变化与慢性反应。我们还将检验假设 前层蛋白A诱导核膜破裂，这可能刺激胞质DNA传感器，并导致细胞凋亡。 炎症的转录程序。我们将从这些体外实验中获得的机械见解 LmnaL 648 R/L 648 R小鼠中受影响细胞的实验。在目标3中，我们将确定前层蛋白A是否实际上 通过检查年轻和老年小鼠的骨骼和血管组织，我们将 还探测人组织阵列和一组来自年轻和老年个体的成纤维细胞的前层蛋白A。 阐明前层蛋白A积累的细胞机制和后果可以改变临床 用于治疗基于前层蛋白A的过早衰老病症的范例。更广泛地说， 该项目可以严格牵连prelamin A在生理老化，确定它作为一个潜在的治疗 针对与年龄相关骨质疏松症、心血管疾病以及可能的其他疾病。