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.

Public Health Relevance

CF is a complex loss-of-function disease caused by genetic and epigenetic variation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). We will focus on understanding spatial relationships defined by genetic diversity across the CF population that are sensitive to Histone DeACetylase (HDAC) activity to understand the role of the acetylation/deacetylation balance in facilitating function in the individual. We will use a combination of genomic/epigenomic/proteomic approaches based on the principles of Variation Spatial Profiling (VSP) and Spatial CoVariance (SCV) to dissect the role of HDAC in integrated pathways that affect CFTR variant synthesis, folding, trafficking and stability/function at the cell surface that may be responsive to chemical and/or biological manipulation of the epigenome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL095524-09A1
Application #
9739114
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Lachowicz-Scroggins, Marrah Elizabeth
Project Start
2010-05-15
Project End
2023-03-31
Budget Start
2019-05-15
Budget End
2020-03-31
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Hutt, Darren M; Loguercio, Salvatore; Roth, Daniela Martino et al. (2018) Correcting the F508del-CFTR variant by modulating eukaryotic translation initiation factor 3-mediated translation initiation. J Biol Chem 293:13477-13495
Wang, Chao; Balch, William E (2018) Bridging Genomics to Phenomics at Atomic Resolution through Variation Spatial Profiling. Cell Rep 24:2013-2028.e6
Hutt, Darren M; Mishra, Sanjay Kumar; Roth, Daniela Martino et al. (2018) Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. J Biol Chem 293:13682-13695
Hutt, Darren M; Loguercio, Salvatore; Campos, Alexandre Rosa et al. (2018) A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease. J Mol Biol 430:2951-2973
Pipalia, Nina H; Subramanian, Kanagaraj; Mao, Shu et al. (2017) Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells. J Lipid Res 58:695-708
Wang, Chao; Bouchecareilh, Marion; Balch, William E (2017) Measuring the Effect of Histone Deacetylase Inhibitors (HDACi) on the Secretion and Activity of Alpha-1 Antitrypsin. Methods Mol Biol 1639:185-193
Veit, Gudio; Avramescu, Radu G; Chiang, Annette N et al. (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424-33
Amaral, Margarida D; Balch, William E (2015) Hallmarks of therapeutic management of the cystic fibrosis functional landscape. J Cyst Fibros 14:687-99
Rauniyar, Navin; Subramanian, Kanagaraj; Lavallée-Adam, Mathieu et al. (2015) Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis. Mol Cell Proteomics 14:1734-49
Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego et al. (2015) ?F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 528:510-6

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