Funding opportunity announcement (FOA) for pilot studies to investigate the role of BLOC1S1 in modulating biological processes relating to atrial fibrillation and age-related hearing impairment
Purpose: The NIA-supported Longevity Genomics (LG) project is pleased to announce the availability of pilot funds for the functional characterization of BLOC1S1 to inform translational research strategies to promote healthy aging. Analyses conducted by the LG suggest that this candidate gene may play important roles in the development of atrial fibrillation and age-related hearing impairment.
Budget limits, duration and number of awards: This is a one-time funding opportunity. Budgets are limited to $45,000 direct costs, indirect costs are supported, and the project period is limited to one year. It is anticipated that 2 pilot awards will be made in response to this FOA.
Application Due Date: August 15, 2020. Maximum length of application: 2 pages (NIH R03 style guide). Standard NIH Biosketch to be included, with budget justification, and timeline of proposed project.
Background: The goal of the NIA-supported Longevity Genomics (LG) project is to facilitate translational studies of Longevity-Associated Genes (LAGs). Further details of this research program are available on our study website (www.longevitygenomics.org). Our approach is to follow-up Longevity-Associated Variants (LAVs) identified from genome-wide association studies (GWAS) of human longevity to identify targets for further exploration/validation.
Members of our research group in a large consortium identified LAVs in a GWAS meta-analysis of longevity (Deelen et al., 2019). To identify LAGs from LAVs, we used S-PrediXcan, an analytic approach that uses tissue-specific eQTL results from the GTEx project to estimate gene-level and tissue-specific associations with the trait examined from summary-level GWA study results, which in our case was human longevity (Barbeira et al. 2018). This analysis identified 14 candidate LAGs (Table 3 in Deelen et al., 2019).
To prioritize these LAGs for functional follow-up, we performed an aging-focused phenome-wide association study (PheWAS) to identify potential effects in humans, both intended and unintended, that could result from the manipulation of LAG activity. Constructing translational strategies solely based on longevity findings can overlook potential adverse events and side-effects, which would not be tolerable for interventions designed to promote healthy aging rather than treating a disease associated with morbidity and mortality.
BLOC1S1 was identified as the most promising candidate LAG from our PheWAS analysis (https://danielevanslab.shinyapps.io/agingPheWAS/). BLOC1S1's trait association profile shows a very limited association profile, which could point to the relative lack of adverse events associated with manipulating BLOC1S1 gene expression. Lower genetically predicted BLOC1S1 expression is associated with higher odds of longevity, lower odds of age-related hearing impairment (ARHI), and lower odds of atrial fibrillation, without the significant association with adverse events. BLOC1S1 displays the best trait association profile of all LAGs described in Table 3 of Deelen et al., 2019 in terms of having beneficial associations with few or no harmful associations.
In this FOA, we are soliciting laboratory investigations that can be performed to functionally test some of our data analysis predictions and assumptions. We are pleased to announce the availability of pilot funds through the LG for the functional characterization of BLOC1S1.
Much of the published work on the biological function of BLOC1S1 has referred to its gene name alias GCN5L1. There is evidence that GCN5L1 regulates TFEB and PGC-1α to maintain cellular mitochondrial content (Scott et al. 2014). Recently, it was shown that GCN5L1 promotes cardiac cell survival by regulating the mTORC2 component Rictor (Manning et al. 2019). Pilot studies examining whether BLOC1S1/GCN5L1’s association with atrial fibrillation, hearing loss, and longevity are due to its role in regulating mitochondrial content, or its regulation of the mTORC2 component Rictor, or perhaps both, are encouraged. It is also possible that a novel biological function of BLOC1S1/GCN5L1 is underlying the human genetic associations.
Examples of potential pilot studies on BLOC1S1 include but are not limited to:
- Examination of hearing function and cardiac conduction in mouse knockout models of BLOC1S1.
- Trait associations can be examined in loss of function mouse models using heterozygous genotypes and/or tissue-specific knockout models.
- Trait associations can also be examined in overexpression models of BLOC1S1.
- Evaluation of molecules/drugs that modulate BLOC1S1 activity in in-vitro model systems and identification of mechanistic pathway(s) associated with BLOC1S1.
Technologies proposed for these investigations may use a wide array of model systems, including but not limited to mouse models, cell culture, iPSC, CRISPR/Cas9, or tissue engineering approaches. Proposed studies must be tightly focused, modest in scope, and address a very specific hypothesis with regard to BLOC1S1.
Applications which do not directly test the functional relevance of BLOC1S1 will be considered as outside the scope of this FOA. Applications using invertebrate model systems will be deemed unresponsive because invertebrates are too phylogenetically distant from humans, the organism from which the gene selection was based.
Merit Review: Applications will be reviewed internally by the Longevity Genomics investigators within one-month from the application deadline.
Review Criteria: The review of proposed pilot studies will be based on a clearly stated hypothesis, appropriately focused and feasibility of proposed approach, and track record of the investigator/research team.
Reporting Requirements: At the completion of the project, the PI will be invited to present the outcomes of their funded research at the annual meeting of the funded U24 program, held in San Francisco, CA or Bethesda, MD. Travel expenses will be reimbursed and do not need to be included in the pilot study budget.
Results from the pilot studies will be posted on the longevitygenomics.org website, and potential programs may use these hits to model age-related pathophysiology.
Inquiries to the FOA: Potential applicants are encouraged to contact Simon Melov (smelov [at] buckinstitute [dot] org) and Dan Evans (Daniel.Evans [at] ucsf [dot] edu) to learn more about this pilot funding opportunity and to discuss their ideas for pilot projects.
Barbeira AN, Dickinson SP, Bonazzola R, Zheng J, Wheeler HE, Torres JM, et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat Commun. 2018 May 8;9(1):1825.
Deelen J, Evans DS, Arking DE, Tesi N, Nygaard M, Liu X, et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat Commun. 2019 Aug 14;10(1):3669.
Manning JR, Thapa D, Zhang M, Stoner MW, Traba J, Corey C, et al. Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling. Biochem J. 2019 Jun 19;476(12):1713–24.
Scott I, Webster BR, Chan CK, Okonkwo JU, Han K, Sack MN. GCN5-like protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy. J Biol Chem. 2014 Jan 31;289(5):2864–72.