Nuclear and chromatin aberrations during non-apoptotic cell death in C. elegans and mammals

线虫和哺乳动物非凋亡细胞死亡过程中的核和染色质畸变

• 批准号: 10723868
• 负责人: Olga Yarychkivska
• 金额: $ 12.5万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723868
• 关键词: Adult; Advisory Committees; Aging; Animals; Apoptosis; Apoptotic; Automobile Driving; Back; Biological Models; Caenorhabditis elegans; Caspase; Cell Count; Cell Death; Cell Death Process; Cell Division Process; Cell Nucleus; Cell division; Cells; Cessation of life; Chromatin; Complex; Cytoskeleton; DNA biosynthesis; Data; Development; Disease; Disseminated Malignant Neoplasm; Ductal Epithelial Cell; Environment; Epigenetic Process; Event; Exhibits; Faculty; Failure; Funding Opportunities; Genes; Genetic; Goals; Heterochromatin; Histone H1; Histone H2B; Histones; Homologous Gene; Huntington Disease; Infarction; Invertebrates; Lamins; Link; Malignant Neoplasms; Mammals; Mentors; Mentorship; Methods; Methyltransferase; Mitosis; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Nerve Degeneration; Nuclear; Nuclear Lamin; Nuclear Lamina; Nuclear Structure; Organ; Organ Culture Techniques; Pathogenesis; Pathologic; Patients; Peripheral; Phase; Phenotype; Physiological; Play; Positioning Attribute; Postdoctoral Fellow; Process; Progeria; Proteomics; Publishing; RNA interference screen; Regulation; Reporter; Research; Research Design; Research Proposals; Role; Science; Solid; Structure of paramesonephric duct; System; Testing; Tissues; Training; Universities; Work; biomarker identification; cell type; chromatin remodeling; clinically significant; confocal imaging; histone modification; human disease; in vivo Model; innovation; insight; male; mouse model; neuron loss; novel; novel marker; physiologic model; polyglutamine; polyglutamine neurodegenerative diseases; post-doctoral training; programs; therapeutic development; tissue degeneration

Project Summary/ Abstract The long-term goal of the proposed research is to uncover molecular mechanisms driving non- apoptotic cell death in vertebrate development and disease, specifically the role of nuclear and chromatin organization in this process. Programed cell death functions to sculpt organs, remodel tissues, regulate cell number, and remove defective cells. While apoptosis is the most studied type of cell death, it does not account for all cellular destruction during development. Studies in C. elegans have uncovered a novel developmental cell death program, referred to as linker cell-type death (LCD), which is morphologically and molecularly distinct from apoptosis. Cell death with LCD features is commonly observed during vertebrate development and in neurodegenerative polyglutamine diseases, aggressive cancers, aging, progeria and laminopathies. During my postdoctoral training, I uncovered striking nuclear and chromatin changes that occur during LCD. This K99/R00 proposal seeks to identify the molecular regulatory processes underlying these nuclear and chromatin changes during LCD in C. elegans, and to test the functional conservation of LCD in a vertebrate context through the following specific aims: 1) Elucidate the role of nuclear lamin and its regulation in the process of LCD (K99); 2) Establish a mouse model system to study LCD in a developmental mammalian setting using degenerating Mullerian duct as a model (K99/R00); 3) Identify molecular processes that govern chromatin dynamics during LCD in C. elegans and mammals (R00). This proposal builds on my doctoral studies in mammalian epigenetics and chromatin, as well as postdoctoral training investigating non-apoptotic cell death in C. elegans. During the mentored phase, I will gain essential training in mouse organ culture and management, which will set me up to establish a robust and innovative independent research program studying the contribution of chromatin and nucleus to the non-apoptotic cell death in vertebrate and invertebrate systems, in addition to human disease. The outstanding environment at the Rockefeller University, with mentorship from Dr. Shaham and my Advisory Committee, will provide crucial expertise to facilitate my transition to independence. The studies proposed here will lead to the development of new markers to distinguish among different types of cell death in vertebrate development and disease, while uncovering the molecular underpinnings of LCD. Because LCD is a prevalent type of cell demise, this proposal may not only shed light on basic aspects of development, neurodegeneration, and cancer, but could also eventually uncover in-roads of clinical significance.

项目概要/摘要 拟议研究的长期目标是揭示驱动非 细胞凋亡在脊椎动物发育和疾病中的作用，特别是细胞核和细胞凋亡的作用 在此过程中染色质组织。程序性细胞死亡具有塑造器官、重塑组织的功能， 调节细胞数量，去除缺陷细胞。虽然细胞凋亡是研究最多的细胞死亡类型，但它 并不能解释发育过程中所有的细胞破坏。对秀丽隐杆线虫的研究发现 新型发育性细胞死亡程序，称为链接细胞型死亡（LCD），其形态学上 并且在分子上与细胞凋亡不同。具有 LCD 特征的细胞死亡在脊椎动物中常见 发育和神经退行性多聚谷氨酰胺疾病、侵袭性癌症、衰老、早衰症和 核纤层蛋白病。在博士后培训期间，我发现了惊人的核和染色质变化 发生在 LCD 期间。该 K99/R00 提案旨在确定分子调控过程 线虫 LCD 过程中这些核和染色质变化的基础，并测试功能 通过以下具体目标来保护脊椎动物中的 LCD：1）阐明其作用 核纤层蛋白及其在 LCD 过程中的调控（K99）； 2）建立小鼠模型系统进行研究 使用退化苗勒氏管作为模型的发育哺乳动物环境中的 LCD (K99/R00)； 3） 识别线虫和哺乳动物 LCD 过程中控制染色质动态的分子过程 (R00)。 该提案建立在我在哺乳动物表观遗传学和染色质方面的博士研究以及博士后研究的基础上 研究线虫非凋亡细胞死亡的培训。在指导阶段，我将获得必要的 小鼠器官培养和管理方面的培训，这将使我建立一个健全和 创新的独立研究计划，研究染色质和细胞核对细胞核的贡献 除了人类疾病之外，脊椎动物和无脊椎动物系统中的非凋亡细胞死亡。这 洛克菲勒大学环境优越，有 Shaham 博士和我的顾问的指导 委员会将提供重要的专业知识，以促进我向独立过渡。提出的研究 这将导致新标记的开发，以区分不同类型的细胞死亡 脊椎动物的发育和疾病，同时揭示 LCD 的分子基础。因为液晶 是一种普遍的细胞死亡类型，该提案不仅可以阐明发育的基本方面， 神经退行性疾病和癌症，但最终也可能揭示具有临床意义的进展。