This competitive renewal retains its specific focus on the role of histone deacetylase (HDAC) activity in cystic fibrosis (CF), building on our substantia progress in the last funding period (2010 to 2014). CF is an inherited loss-of-function disease caused principally by a Phe508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR), referred to as F508del. We are now beginning to appreciate the importance of many other mutations in providing insights into synthesis, folding, trafficking and stability/function pathways that will be addressed in this competitive renewal focused on the deacetylation ('eraser') biology of HDAC7 in correcting F508del. CFTR is a multi-membrane spanning, cAMP-regulated chloride channel. Misfolding of F508del, and likely many other mutants, reduce the synthesis, folding, trafficking and/or stability/function of CFTR resulting in the loss of cell surface conductance, premature lung failure and shortened lifespan. As such, CF is a disease of proteostasis biology as we have demonstrated under auspices of the previous funding period and in the past. Proteostasis is the cellular environment that maintains the proteome for normal cellular function. It is frequently adjusted using multiple signaling pathways to protect the cell from protein folding stress during transient insult and in response to inherite, chronic misfolding diseases. The thrust of this competitive renewal is to seek correction of CF through an understanding HDAC7 deacetylation function. During the last funding period we provided evidence that HDACs, particularly HDAC7, can exert control through multiple avenues- transcriptional, translational and/or co-/post-translational programs that are linked to different components of the proteome through acetylation/deacetylation pathways. These can operate together to achieve a level of stability and function of F508del that can be protective and corrective for CF. Herein, we propose to focus on the enabling working hypothesis that the stability and function of wild-type (WT) and F508del CFTR is strongly influenced by the HDAC7 network of deacetylation activities that operate through transcriptional, translational and/or co-/post-translational mechanisms to direct protein function, and that the HDAC7 specific network can be manipulated to provide a protective environment for CF in the clinic. To explore our working hypothesis, we propose two aims:
Aim 1 focuses on understanding the role of new targets revealed by the HDAC7 interactome generated during the last funding period that are likely responsible for HDAC7 function in correction of CF;
Aim 2 focuses on approaches to understand the role of HDAC7 in (re)balancing acetylation-deacetylation pathways involved in correcting CF variants. The combined Aims will provide systematic approach to address HDAC7 regulated pathways affecting F508del synthesis, folding, trafficking and stability/function at the cell surface. They will provide an in-depth link to the cyclical acetylation- deacetylation environments regulated by HDAC7 that may be corrective for CF disease in the clinic

Public Health Relevance

CF is an inherited loss-of-function disease caused principally by a Phe508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR) (F508del-CFTR). In this proposal we will address the role of protein acetylation-deacetylation cycles managed by histone deacetylase 7 (HDAC7) in the correction of CF. To accomplish this goal, we will focus on understanding the function of new targets revealed by the HDAC7 interactome that are likely responsible for correction, and we will use a variety of approaches to understand their specific roles in integrated pathways that affect F508del synthesis, folding, trafficking and stability/function at the cell surface that may be corrective for CF disease in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL095524-05
Application #
8761533
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Smith, Robert A
Project Start
2009-04-01
Project End
2018-06-30
Budget Start
2014-08-05
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$473,750
Indirect Cost
$223,750
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Powers, Evan T; Balch, William E (2013) Diversity in the origins of proteostasis networks--a driver for protein function in evolution. Nat Rev Mol Cell Biol 14:237-48
Hutt, Darren M; Balch, William E (2013) Expanding proteostasis by membrane trafficking networks. Cold Spring Harb Perspect Biol 5:
Gupta, Vijay; Balch, William E (2013) Protein folding: salty sea regulators of cystic fibrosis. Nat Chem Biol 9:12-4
Hutt, Darren M; Balch, William E (2013) Expanding proteostasis by membrane trafficking networks. Cold Spring Harb Perspect Med 3:1-21
Powers, Evan T; Balch, William E (2013) Diversity in the origins of proteostasis networks--a driver for protein function in evolution. Nat Rev Mol Cell Biol 14:237-48
Calamini, Barbara; Silva, Maria Catarina; Madoux, Franck et al. (2012) Small-molecule proteostasis regulators for protein conformational diseases. Nat Chem Biol 8:185-96
Hutt, Darren M; Olsen, Christian A; Vickers, Chris J et al. (2011) Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides that Restore Trafficking and Activity of ?F508-CFTR. ACS Med Chem Lett 2:703-707
Peters, Kathryn W; Okiyoneda, Tsukasa; Balch, William E et al. (2011) CFTR Folding Consortium: methods available for studies of CFTR folding and correction. Methods Mol Biol 742:335-53
Balch, William E; Roth, Daniela M; Hutt, Darren M (2011) Emergent properties of proteostasis in managing cystic fibrosis. Cold Spring Harb Perspect Biol 3:
Zhang, Xiaoping; Dong, Chunmin; Wu, Qiong J et al. (2011) Di-acidic motifs in the membrane-distal C termini modulate the transport of angiotensin II receptors from the endoplasmic reticulum to the cell surface. J Biol Chem 286:20525-35

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