Modulation of Lung Disease by Genetic/Epigenetic Profiling

项目总结/摘要 以囊性纤维化（CF）功能丧失为特征的肺部疾病的治疗管理 导致CF的跨膜电导调节因子（CFTR）受到遗传和表观遗传的挑战 在CF人群中发现的多样性。精准医疗计划（Precision Medicine Initiative）：All of Us for You （https：//allofus.nih.gov/）以及在患者中发现的大量基因组和表型多样性， 普遍认识到，我们必须找到新的方法来解决CF演示文稿中的复杂性， 诊所这将需要了解决定出生时发病的基本原则， 家族遗传变异及其进展，受表观遗传程序的影响，两者都是个体独有的。 这个建议是关于理解遗传和表观遗传多样性在CF中的作用， 去乙酰化酶（HDAC）活性。我们已经证明这些关系对HDAC的活性有反应， 管理基因组和蛋白质组（表观基因组）乙酰化/脱乙酰化平衡的蛋白质 整合基因组与蛋白质组和表型组之间的复杂功能。依据的前提 基因组和表观基因组对操纵敏感，所述操纵将有利于增加基因组和表观基因组的功能。 CFTR变体折叠，该提案的目的是机械地定义HDAC调制对 在工作台和床旁观察CFTR功能。我们假设，CF可以最好地理解基于 基于这样的理论，即疾病可以通过CF人群中发现的改变 个体中CFTR序列-功能-结构关系，如现在使用空间变异描述的 分析（VSP）和空间协方差（SCV）的新原理（Wang和Balch，2018，出版中）。是 本研究的目的是应用VSP/SCV分析表观基因组在CF中的作用。关键目标是 在这个建议中实现的是1）定义分子，细胞和生理状态，2）描述的作用， CF群体中的遗传/表观遗传/蛋白质组多样性，以3）提供序列-功能-结构 疾病在个体中的表征。目的1将探索HDAC抑制剂（HDACi）的影响，以确定， 从生物化学/遗传多样性的角度来看，整个CF群体的变化将如何应对 乙酰化/脱乙酰化动力学的再平衡。目标2将重点关注HDAC 7在管理 CF遗传多样性的分子，生物化学和细胞的方法。目标3将分析选择的作用 HDAC 7敏感性CFTR相互作用物，以解决它们在管理来自表观遗传学的CF变异中的作用。 perspective.我们假设这些目标的完成将描述人群中的关系 定义了影响个体CF进展的表观基因组连锁基因组特征。我们的集成 基因组/表观基因组/蛋白质组平台将促进我们对遗传多样性在人类遗传多样性中的贡献的理解。 CF作为一种复杂疾病的进展和管理。

Project Summary/Abstract Therapeutic management of lung disorders hallmarked by the loss-of-function of the Cystic Fibrosis (CF) Transmembrane conductance Regulator (CFTR) leading to CF are challenged by genetic and epigenetic diversity found in the CF population. Given the Precision Medicine Initiative (All of Us for You (https://allofus.nih.gov/) and the large amount of genomic and phenomic diversity found in patients, it is now generally recognized that we must find new approaches to address the complexity in CF presentation in the clinic. This will require an understanding of fundamental principles dictating disease onset at birth, defined by familial genetic variation, and its progression, influenced by epigenetic programs, both unique to the individual. This proposal is about understanding the role of genetic and epigenetic diversity in CF in response to Histone DeACetylase (HDAC) activity. We have shown these relationships to be responsive to the activity of HDACs, proteins that manage the acetylation/deacetylation balance of the genome and the proteome (the epigenome) to integrate the complex functions linking the genome to the proteome and phenome. Based on the premise that the genome and epigenome are sensitive to manipulation(s) that will favor increased functionality of the CFTR variant fold, the objective of this proposal is to mechanistically define the impact of HDAC modulation on CFTR function observed at the bench and the bedside. We hypothesize that CF can be best understood based on the rationale that disease can be defined by the collective of variation found in the CF population that alters CFTR sequence-to-function-to-structure relationships in the individual as now described using Variation Spatial Profiling (VSP) and the new principle of Spatial CoVariance (SCV) (Wang and Balch, 2018, In press). It is the objective of this proposal to apply VSP/SCV to analysis of the role of the epigenome in CF. Key goals to be achieved in this proposal are to 1) define molecular, cellular and physiological states that 2) describe the role of genetic/epigenetic/proteomic diversity in the CF population to 3) provide a sequence-to-function-to-structure characterization of disease in the individual. Aim 1 will explore the impact of HDAC inhibitors (HDACi) to define, from a biochemical/genetic diversity perspective, how variation across the entire CF population will respond to rebalancing of acetylation/deacetylation dynamics. Aim 2 will focus on the role of HDAC7 in the management of CF genetic diversity using molecular, biochemical and cellular approaches. Aim 3 will analyze the role of select HDAC7-sensitive CFTR interactors to address their role in the management of CF variation from an epigenetic perspective. We hypothesize that the completion of these Aims will describe relationships in the population that define the epigenome-linked genome features that impact progression of CF in the individual. Our integrated genome/epigenome/proteome platform will advance our understanding of the contribution of genetic diversity in the progression and management of CF as a complex disease.