# Modulation of Lung Disease by Genetic/Epigenetic Profiling

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $483,750

## Abstract

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...

## Key facts

- **NIH application ID:** 9928091
- **Project number:** 5R01HL095524-10
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** William Edward Balch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,750
- **Award type:** 5
- **Project period:** 2010-05-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928091

## Citation

> US National Institutes of Health, RePORTER application 9928091, Modulation of Lung Disease by Genetic/Epigenetic Profiling (5R01HL095524-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928091. Licensed CC0.

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