Age-associated chromatin changes in hematopoiesis

描述（由申请人提供）：申请人描述了一个为期五年的职业发展计划，导致对造血系统老化中表观遗传机制的作用进行独立的学术调查。虽然申请人以前的研究经验涉及生物系统的定量分析，包括模式生物中表观遗传组织的研究，但这些计算研究集中在基因组的一般组织和调控原则上。拟议的研究和培训计划将使申请者能够集中研究与人类健康直接相关的一系列问题。培训将为申请人提供必要的实验室技能和造血系统，年龄相关的病理学和组织稳态机制的深入了解。拟议的研究计划将对影响小鼠模型中造血各个阶段的年龄相关表观遗传改变进行实验和定量分析，为进一步有针对性地调查年龄相关病理学提供重要起点，并使申请人成为该领域的独立科学家。在美国，高龄是导致心脏病、癌症和其他主要死亡原因的主要危险因素。衰老与多个器官系统的进行性功能衰退和组织功能的广泛破坏有关。伴随衰老的造血组织的变化对个体的健康具有显著的不利影响，导致免疫系统功能的整体下降，自身免疫性和骨髓增生性疾病的发病率增加。这种进展背后的复杂生物学机制仍然知之甚少，但已知涉及造血某些水平的表观遗传状态的变化。拟议的研究将检查表观遗传状态的特定方面，以确定这些变化的性质和范围，以及它们在与年龄相关的造血组织衰退中所起的作用。该研究将测试表观遗传沉默机制活性的总体变化，特别是在异染色质区域的维持方面。它将推断受影响的基因，表观遗传和调控途径，以构建造血不同阶段年龄相关进展的综合模型。然后，该研究将使用这些结果来确定在减少衰老表型的热量限制条件下受影响的动物的正常造血衰老的方面。 公共卫生相关性：造血系统中的依赖性变化导致血细胞功能受损，导致向所有组织输送氧气减少，免疫缺陷，自身免疫和骨髓增生性疾病。这些条件下的复杂的生物学机制仍然知之甚少，但已知涉及表观遗传状态的变化，需要进一步调查。了解造血系统中这些表观遗传改变的分子机制对于开发可以促进健康衰老的预防和治疗措施至关重要。

DESCRIPTION (provided by applicant): The applicant describes a five-year career development plan leading to independent academic investigations on the role of epigenetic mechanisms in aging of the hematopoietic system. While the applicant's previous research experience has involved quantitative analysis of biological systems, including investigations of epigenetic organization in model organisms, these computational studies have concentrated on general organization and regulatory principles of genome. The proposed research and training plan will allow the applicant to focus on a set of problems directly relevant to human health. The training will provide the applicant with necessary laboratory skills and in-depth knowledge of the hematopoietic system, age-associated pathologies and mechanisms involved in tissue homeostasis. The proposed research program will conduct experimental and quantitative analysis of age-associated epigenetic alterations affecting various stages of hematopoiesis in a mouse model, providing an important starting point for further targeted investigations of age-linked pathologies, and allowing the applicant to establish himself as an independent scientist in this field. Advanced age is a major risk factor contributing to heart disease, cancer and other leading causes of deaths in the United States. Aging is associated with progressive functional decline of multiple organ systems and a widespread disruption of tissue functions. Changes in the hematopoietic tissues that accompany aging have significant detrimental impact on the individual's health, resulting in overall decline of the function of the immune system, increased incidence of autoimmune and myloproliferative diseases. The complex biological mechanisms underlying this progression remain poorly understood, but are known to involve changes in the epigenetic state at some levels of hematopoiesis. The proposed research will examine specific aspects of the epigenetic state, to determine the nature and scope of these changes, and the role they play in age-associated decline of hematopoietic tissues. The study will test for global alterations in the activity of epigenetic silencing mechanisms, in particular with respect to maintenance of heterochromatic regions. It will infer affected genes, epigenetic and regulatory pathways to construct integrative models of age-associated progression at different stages of hematopoiesis. The study will then use these results to identify the aspects of normal hematopoietic aging affected in animals under caloric restriction conditions that attenuate aging phenotypes. PUBLIC HEALTH RELEVANCE: Age-dependent changes in hematopoietic system, leading to compromised blood cell functions, result in reduced delivery of oxygen to all the tissues, immunodeficiency, autoimmune and myeloproliferative diseases. The complex biological mechanisms underlying these conditions remain poorly understood, but are known to involve changes in the epigenetic state, requiring further investigation. Understanding the molecular mechanisms of these epigenetic alterations in the hematopoietic system will be important for the development of prophylactic and therapeutic measures that could promote healthy aging.