Funding opportunity announcement (FOA) for pilot studies to investigate the role of CEACAM19 or ADAMTS7 in modulating healthy aging.
Purpose: The NIA-supported Longevity Genomics (LG) project is pleased to announce the availability of pilot funds for the functional characterization of CEACAM19 and ADAMTS7 to inform translational research strategies to promote healthy aging. Analyses conducted by the LG suggest that these candidate genes may play important roles in cardiovascular and pulmonary health.
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: April 4, 2019. 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 GWAS of longevity to identify targets for further exploration/validation. By integrating multiple lines of evidence, including eQTL studies, positional overlap, and chromatin interaction studies, we linked LAVs to candidate longevity associated genes (LAGs). However, to identify targets which may ultimately be exploited in drug development for healthy aging, more information is needed beyond an association with long life. We used Mendelian Randomization (MR) analysis to evaluate the potential impact of modulating tissue-specific LAG expression on subclinical risk and disease processes related to human longevity. 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 CEACAM19 and ADAMTS7. Analyses conducted by the LG suggest that these candidate genes may play important roles in cardiovascular and pulmonary health.
We are requesting applications for pilot studies on the two most promising candidates identified to date - CEACAM19 and ADAMTS7.
- CEACAM19 - Carcinoembryonic antigen related cell adhesion molecule 19 (CEACAM19) is a cell-adhesion molecule that is expressed in multiple human tissues, including the aorta (gtexportal.org). CEACAM19 is a member of the Immunoglobulin (Ig) gene family (Pavlopoulou & Scorilas, 2014) that mediates homotypic and heterotypic cell adhesion. Cell adhesion in vascular endothelial cells plays a role in the regulation of inflammation (Rahimi, 2017). We followed-up a recent GWAS of parental lifespan from the UK Biobank data (7,182 parental longevity cases and 79,767 controls) (Pilling et al., 2017). PrediXcan was used to identify associations between tissue-specific genetically predicted gene expression and healthy aging traits in 3 longitudinal cohorts of elderly individuals (MrOS, SOF, Health ABC, total N = 9,893). Findings from our analyses indicate that CEACAM19, which has not previously been implicated in vascular endothelial cell adhesion and inflammation, may play a role in this process, which in turn, may play a role in modulating human longevity.
- ADAMTS7:ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7) is widely expressed across human tissues except for brain tissues. ADAMTS7 is being actively pursued as a target for intervention to possibly reduce the risk of coronary artery disease. It has been posited that inhibiting the function of ADAMTS7 could mimic the cardioprotective effect of ADAMTS7 genetic variants (Pu et al. 2013). A mouse knockout (KO) of ADAMTS7 has been produced, and these mice display no obvious phenotypes and reproduce normally (Bauer et al. 2015). However, in hyperlipidemic mouse models (LDLR or ApoE KOs), ADAMTS7 KO did reduce atherosclerosis (Bauer et al. 2015). In our PrediXcan analysis described above, higher predicted expression of ADAMTS7 in the spleen was associated with better lung function, and smoking status did not confound or interact with the association.
Applicants are encouraged to develop novel pilot studies that focus on validating the role of CEACAM19 and ADAMTS7 in aging. Examples of potential pilot studies on CEACAM19 and ADAMTS7 include but are not limited to:
- Knockdown of CEACAM19 in blood vessels followed by measurement of circulating CRP in the mouse. Mechanistic studies could examine whether CEACAM19 knockdown impacts arterial tissue cell adhesion, and whether alternative experimental manipulation of cell adhesion might have a similar effect on circulating CRP.
- Determine whether CEACAM19 expression changes with age in blood vessels using human tissue or model organisms
- Evaluation of molecules/drugs that modulate CEACAM19 activity in in-vitro model systems and identification of mechanistic pathway(s) associated with CEACAM19.
- Examination of lung function in ADAMTS7 KO mice
- Examination of size, morphology and function of spleen in ADAMTS7 KO mice
- Mechanistic evaluation of ADAMTS7 in lung tissue chips to examine cardiovascular or lung protective roles of ADAMTS7
Technologies proposed for these investigations may use a wide array of model systems, including but not limited to cell culture, iPSC technology, CRISPR/Cas9, or tissue engineering approaches. Proposed studies must be tightly focused, modest in scope, and ask and answer a very specific question with regards to the candidate genes.
Applications which do not directly test the functional relevance of CEACAM19 or ADAMTS7 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 (devans [at] psg [dot] ucsf [dot] edu) to learn more about this pilot funding opportunity and to discuss their ideas for pilot projects.
Pavlopoulou, A., & Scorilas, A. (2014). A comprehensive phylogenetic and structural analysis of the carcinoembryonic antigen (CEA) gene family. Genome Biology and Evolution (6), 1314–1326.
Pilling, L. C., Kuo, C.-L., Sicinski, K., Tamosauskaite, J., Kuchel, G. A., Harries, L. W., … Melzer, D. (2017). Human longevity: 25 genetic loci associated in 389,166 UK biobank participants. Aging, 9(12), 2504–2520.
Rahimi, N. (2017). Defenders and Challengers of Endothelial Barrier Function. Frontiers in Immunology, 8, 1847.
Pu et al (2013). ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant, Am J Hum Genet, 92, 366-374.
Bauer et al, (2015). Knockout of Adamts7, a novel coronary artery disease locus in humans, reduces atherosclerosis in mice, Circulation. 2015 Mar 31;131(13):1202-1213.