Modulation of Lung Disease by Genetic/Epigenetic Profiling

项目概要/摘要： 囊性纤维化（CF）功能丧失引发的肺部疾病的治疗管理 跨膜传导调节因子（CFTR）在导致CF的应答中的功能受到遗传学的挑战。 和表观遗传多样性。高效的调制器疗法（HEMT）Trikafta 对临床疾病病理学的显著但不完全和可变的影响。我们现在需要 发现新的方法来进一步改善临床结果。CF不是一种简单的单基因疾病， 这是一种受CFTR的膜运输和通道功能影响的复杂疾病， 特征包括炎症、粘膜纤毛清除和细菌感染。这些环境特征 疾病导致肺功能障碍以及包括胰腺和肠功能障碍的多器官症状。 新的方法捕捉基因型和细胞功能障碍表型之间的联系， 个体中协变事件的集合将需要对基本原理有更深入的理解 决定疾病受人口的遗传和表观遗传多样性的影响。这项提案是关于 了解表观遗传环境在CF管理中的作用， 脱乙酰酶（HDAC）程序控制发育、衰老和细胞凋亡过程中的基因表达。 疾病中的压力在上一个资助期间，我们已经表明， CF群体可用于定义响应HDAC的序列-功能-结构关系 抑制剂（HDACi）。我们将研究遗传和表观遗传多样性的相互联系的作用，使用新的机器 我们在上一个资助期开发的学习计算方法，可以与 实验/临床特征，以发现可以显著改善患者健康的治疗方法， 对HEMT Trikafta的响应。了解CF中复杂的表观遗传途径的影响，以改善 Trikafta的性能，我们将应用我们新的高斯过程（GP）为基础的平台，称为变异 基于变异捕获（VarC）映射的空间剖析（VSP），以在原子上在残基-残基基础上剖析 解析一个隐藏的空间协变（SCV）相互作用的映射，可以解析复杂的表型关系 遗传/表观遗传多样性的反应。在上一个资助期间，VSP/VarC绘图显示， 隐藏在CFTR折叠中的“YKDAD”能量核心，这是大多数人疾病的基础。 HEMT Trikafta未纠正的CF人群-限制了其在临床中的影响。在目标1中，我们将使用 VSP/VarC映射，以告知我们CFTR错误折叠，贩运和 功能影响炎症，粘膜纤毛清除和感染，以预测如何更有效地治疗 患者通过使用HDAC抑制剂（HDACi）。在目标2中，我们将专门探讨HDAC 7的作用， 我们之前已经证明了纠正CFTR功能。我们假设对HDAC作用的了解 表观遗传程序可用于增强HEMT在治愈途径中的功效。

Project Summary/Abstract: Therapeutic management of lung disorders triggered by the loss-of-function of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) function in response to leading to CF are challenged by genetic and epigenetic diversity found in the CF population. The highly effective modulator therapy (HEMT) Trikafta has a pronounced but incomplete and variable impact on the pathology of disease in the clinic. We now need to discover new approaches to further improve clinical outcome. CF is not a simple monogenic disease but rather a complex disease impacted by membrane trafficking and channel function of CFTR- as well as diverse clinical features including inflammation, mucociliary clearance, and bacterial infection. These environmental features of disease lead to lung dysfunction as well as multi-organ symptoms including pancreatic and intestinal dysfunction. New approaches that capture the link between the genotype and cellular dysfunctional phenotypes as a collective of covariant events in the individual will require a deeper understanding of the fundamental principles dictating disease influenced by genetic and epigenetic diversity of the population. This proposal is about understanding the role of the epigenetic environment in management of CF in response to the histone deacetylase (HDAC) program controlling gene expression during development, aging and in response to cellular stress in disease. During the previous funding period, we have shown that the collective of variation found in the CF population can be used to define sequence-to-function-to-structure relationships responsive to HDAC inhibitors (HDACi). We will study the interlinked roles of genetic and epigenetic diversity using novel machine learning computational approaches we developed during the previous funding period that can be integrated with experimental/clinical features to discover therapeutics that could considerably improve patient well-being in response to the HEMT Trikafta. To understand the impact of complex epigenetic pathways in CF to improve Trikafta performance, we will apply our new Gaussian process (GP) based platform, referred to as variation spatial profiling (VSP) based variation capture (VarC) mapping, to profile at a residue-residue basis at atomic resolution a map of hidden spatial covariant (SCV) interactions that can resolve complex phenotypic relationships in response to genetic/epigenetic diversity. During the previous funding period, VSP/VarC mapping revealed a hidden ‘YKDAD’ energetic core in the CFTR fold that is the foundational basis for disease in the majority of the CF population that is not corrected by the HEMT Trikafta- limiting its impact in the clinic. In Aim 1 we will use VSP/VarC mapping to inform us of the complex disease states disrupted by CFTR misfolding, trafficking and function affecting inflammation, mucociliary clearance and infection to predict how to more effectively treat the patient through use of HDAC inhibitors (HDACi). In Aim 2, we will specifically explore the role of HDAC7, which we have previously shown to correct CFTR function. We hypothesize that knowledge of the role of the HDAC epigenetic program can be used to enhance HEMT efficacy in the path to a cure.