Validation of Nuclear Morphology as a Biomarker of Aging and Aging-Related Phenotypes

核形态作为衰老和衰老相关表型生物标志物的验证

基本信息

批准号：
10424439
负责人：
Denis Wirtz
金额：
$ 58.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424439
关键词：
Actins Adhesives Age Aging American B-Lymphocytes Biological Biological Markers Biomechanics Cell Aging Cell Nucleus Cell physiology Cells Cellular Morphology Cessation of life Characteristics Chronic Disease Chronology Clinical Complex Data Dermal Dermatology Dermatopathology Descriptor Development Discrimination Disease Elderly Etiology Fibroblasts Gender Human Individual Institutes Interphase Lamin Type A Lamins Lymphocyte Measurement Measures Molecular Morphology Nuclear Nuclear Lamin Nuclear Protein Outcome Participant Patient Recruitments Patients Pharmacology Phenotype Population Study Prospective cohort study Proteins Race Research Research Personnel Resources Risk Shapes Source Squamous Cell Structure Technology Testing Tissues Universities Validation age related aging population behavioral health biomarker validation biophysical techniques cohort frailty healthy aging multiple chronic conditions nanobiotechnology novel protein expression protein structure recruit single cell technology

项目摘要

Abstract Alterations in the nuclear protein lamin and associated structures in the nucleus have been identified as a source of nuclear morphology changes that markedly impact overall cellular function. These changes in nuclear morphology are thought to drive molecular changes that influence a wide range of aging-related phenotypes and chronic disease states. Importantly, we have recently used high-throughput measurements of nuclear morphology to identify outstanding biomarkers of chronological age. We hypothesize that these age-related changes in nuclear morphology are highly correlated with chronological age in healthy individuals, and that a specific age-related biological change in lamin underlies this phenomenon. Building on our prior development of these high-throughput and accurate measures of nuclear morphology, we propose here to further develop this biological discovery and technology as a valid and reliable biomarker of aging-related biological mechanisms. We hypothesize that changes in nuclear morphology can be rapidly measured and that age-related alterations correlate with aging-related phenotypes and disease states independently of chronological age, consistent with a measure of cellular biological age. To test these hypotheses and move results toward clinical utility, we have assembled a highly synergistic, interdisciplinary team propose the following specific aims: Aim 1. Using our validated single-cell technologies, we will develop a mechanistic understanding of how descriptors of nuclear morphology in human dermal fibroblasts and B-lymphocytes are robust biomarkers of aging in healthy individuals. Aim 2. Establish the accuracy and precision with which our proposed biomarkers identify chronological age for individuals with varying demographic, behavioral, and health characteristics. Aim 3. We will examine the strength with which morphological biomarkers discriminate individuals with adverse phenotypes and outcomes of aging, and at risk for the development of these, from healthy older adults, above and beyond chronological age.

抽象的核蛋白核纤层蛋白和细胞核中相关结构的改变已被证实被确定为显着影响整个细胞的核形态变化的来源功能。核形态的这些变化被认为驱动了分子变化，影响广泛的与衰老相关的表型和慢性疾病状态。重要的是，我们最近使用核形态的高通量测量来识别突出的实际年龄的生物标志物。我们假设这些与年龄相关的核变化形态学与健康个体的实际年龄高度相关，并且特定的核纤层蛋白中与年龄相关的生物变化是这种现象的基础。建立在我们之前的基础上开发这些高通量和准确的核形态测量方法，我们建议在这里进一步发展这一生物发现和技术作为有效和可靠的生物标志物衰老相关的生物学机制。我们假设核形态的变化可以可以快速测量，并且与年龄相关的改变与与衰老相关的表型相关，并且疾病状态与实际年龄无关，与细胞生物学测量一致年龄。为了测试这些假设并将结果推向临床实用性，我们组装了一个高度协同、跨学科团队提出以下具体目标：目标 1. 使用我们经过验证的单细胞技术，我们将深入了解机制人类真皮成纤维细胞和 B 淋巴细胞核形态描述符的描述方式健康个体衰老的强大生物标志物。目标 2. 建立准确性和精密度我们提出的生物标志物可以识别具有不同年龄的个体的实际年龄人口、行为和健康特征。目标 3. 我们将检查强度哪些形态学生物标志物可以区分具有不良表型和结果的个体健康老年人的老龄化问题，以及面临这些问题发展的风险实际年龄。