SPECIAL NOTICE
99 -- Functional Genomics as a Discovery Tool for Hearing Health
- Notice Date
- 7/10/2023 5:53:53 AM
- Notice Type
- Special Notice
- NAICS
- 611710
— Educational Support Services
- Contracting Office
- NATIONAL INSTITUTES OF HEALTH OLAO BETHESDA MD 20892 USA
- ZIP Code
- 20892
- Solicitation Number
- NIHODSS071023
- Response Due
- 7/14/2023 9:00:00 AM
- Archive Date
- 07/29/2023
- Point of Contact
- Sharmaine Fagan, Phone: 3015943744
- E-Mail Address
-
sharmaine.fagan@nih.gov
(sharmaine.fagan@nih.gov)
- Description
- Notice of Intent to Sole Source for Functional Genomics as a Discovery Tool for Hearing Health. Special Notice # NIHODSS071023 The National Institutes of Health (NIH) intends to award a Firm-Fixed-Price contract �to Tel Aviv University for Functional Genomics as a Discovery Tool for Hearing Health. In accordance with FAR Part 6.302-1, the Contractor is the only known responsible source who can develop bioinformatics methodologies and tools required for the analysis of the transcriptomics and epigenomics per SOW below. This notice is not a request for competitive quotes.� However, any party that believes it can provide the services as� stated herein may submit a written capability statement that clearly supports and demonstrates their ability to satisfy the requirement. A determination by the Government to compete this proposed award based upon responses to this notice is solely within the discretion of the Government. It is anticipated that an award will be issued approximately five (5) days after the date of this notice unless the Government determines that another organization has the capability to meet this requirement. � Please email responses to Sharmaine.fagan@nih.gov� no later than 12:00 p.m. EST on Friday July 14, 2023. SOW - Collaboration with Elkon�s lab � Tel Aviv University (TAU) Background The longstanding collaboration with Dr. Ran Elkon is ongoing now for over two decades. This is an intimate experimental-computational collaboration that combines Dr. Hertzano's expertise in hearing research, specifically in bulk and cell-type specific omics techniques, and Dr. Elkon�s expertise in bioinformatics and development of analytical methods for various omics datasets. Elkon�s lab is among the leading research groups worldwide to apply cutting-edge bioinformatics analyses for improving our understating of cochlea development. Throughout the years, our very fruitful collaboration yielded manifold impactful discoveries on transcriptional programs that determine cell identity in the inner ear and resulted in many joint high-impact publications1�7. In our collaboration with Dr. Elkon, establishment of animal and cellular systems and generation of omics data are done in Dr. Hertzano lab, while computational techniques for omics analysis are developed and implemented in Elkon�s lab in Tel Aviv University (TAU). Bioinformatics data analysis is done jointly by our two labs, under the supervision of Dr. Elkon. The work is synergistic, and its success depends on this mutual reliance. The two teams work in the forefronts of their respective fields, and through shared leadership and guidance design the experiments and perform the analyses. In the experience of the Hertzano team, similar results were not possible when contracting with core-facility bioinformatics teams. The in-depth involvement of Elkon�s lab in all aspects of experimental design, collaborative development of tools, analysis of data and interpretation of the results was critical for both our previous discoveries and ongoing studies. This unique interlink with Dr. Elkon�s computational lab is a mainstay of the discoveries done by Hertzano�s lab over the last decade, which puts our team in a leading position in inner ear research.��� Purpose and Objectives of the procurement The purpose of this procurement is to benefit from the expertise of Dr. Elkon and his research associates in TAU and enable the continuation of the productive collaboration with Dr. Hertzano lab. The specific objectives of this procurement for the coming 5 years are: Delineation of hair cell (HC) specific transcriptional networks during development.��� Dr. Elkon develops bioinformatics methods for delineation of transcriptional networks from transcriptomic and epigenomic data and statistical approaches for prediction of links between distal regulatory elements (mostly, enhancers) and their target promoters (enhancer-promoter links (E-P links)) 3,8�12. By applying these computational methods to transcriptomics and epigenomics cell type-specific datasets generated in Hertzano�s lab, we will systematically identify transcriptional programs and transcription factors (TFs) that determine cell fate in the cochlea, with specific emphasis on the delineation of the programs that dictate outer and inner HC differentiation and maturation. Improving our understanding the genetic basis of age-related hearing loss (ARHL). Elkon�s lab also develops bioinformatics approaches for enhancing the functional interpretation of results obtained by genome-wide association studies (GWAS) based on integrated analysis with transcriptomic and epigenomic data collected in cell types relevant for the pathophysiology of the disease/trait13�17. A major challenge stems from the fact that the majority of genetic variants identified by GWAS for any complex disease map to the noncoding portion of the human genome, and presumably acting by interfering with gene regulation. GWAS applied to ARHL found dozens of variants (mostly noncoding) associated with increased risk for hearing impairments among the elderly population. Elkon�s lab will combine the analysis of ARHL GWAS data with single-cell and single-nucleus transcriptomic/epigenomic data generated by Hertzano�s lab to identify specific genes, molecular pathways and cell types that are affected by the ARHL-predisposing genetic variants. Define cell type-specific and sex-specific responses to noise. A third long-term study done in collaboration with Dr. Elkon is aimed at understanding the molecular basis of noise-induced hearing loss (NIHL), including the identification of specific pathways involved in the sex-specific response to noise. Here too, our experimental-computational strategy is based on the analysis of large-scale omics profiles. Elkon�s lab will analyze the datasets measured in male and female mice in response to noise, to comprehensively identify shared transcriptional programs and cell type-specific pathways induced upon noise exposure. Once these pathways are defined, we will cross them with large drug-target DBs, aiming to detect FDA-approved drugs that could potentially have a protective effect against noise exposure4. Contractor deliverables In each of the studies listed above, data analysis will be led and supervised by Elkon�s lab, in close collaboration with the experimentalist from Hertzano�s lab who generated the data. Specific deliverables in each project: Delineation of hair cell (HC) specific transcriptional networks during development 1a. Global E-P maps for the cochlea 1b. Candidate TFs that regulate cell fate of key cell types in the cochlea 1c. Candidate target genes regulated by each candidate TF 1d. Biological processes performed by each transcriptional module (TF + candidate genes) 1e. Combinations of TFs that form combinatorial gene regulation (cis-regulatory modules) in the cochlea Improving our understanding the genetic basis of age-related hearing loss (ARHL) 2a. Genes enriched for ARHL risk variants 2b. Molecular pathways and biological networks enriched for ARHL risk variants 2c. Cell-types and developmental stages in which ARHL �risk genes� exert their biological function� Define cell type-specific and sex-specific responses to noise 3a. Common and sex-specific noise-responsive genes (shared and cell-type specific) 3b. Common and sex-specific biological pathways induced upon noise exposure 3c. Mediators of sex-specific responses 3d. FDA-approved drugs that potentially modulate the activity of noise-induced pathways Government responsibilities - what we provide The analysis done in Elkon�s lab will be based on single-cell RNA-seq and single-nucleus ATAC-seq datasets that will be generated in Hertzano�s lab, in wild-type and genetically manipulated mouse models, under na�ve conditions and after exposure to noise (in both sexes). Full raw data (fastq and bam files) will be provided to Elkon�s lab. � Reporting requirements and deliverables In all projects, full data from all analyses phases will be provided to Hertzano�s lab. When applicable, final results will be made publicly available to the research community through the gEAR platform, developed by Hertzano�s lab. Program Mgmt. and Control requirements Hertzano and Elkon labs will maintain regular teleconference meetings every 3-4 weeks headed by the two PIs to discuss the analysis and results and supervise progress of the projects. In addition, researches from the two labs will be in a continuous direct contact as the data analysis proceeds. Dr. Elkon will be responsible for monitoring and proper accounting of expenditures in TAU. ��� Inspection and Acceptance Criteria Dr. Hertzano will inspect the analysis progress and results through the regular teleconference meetings that the two labs will maintain. References 1.������� Hertzano, R. et al. Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis. PLoS Genet. 7, e1002309 (2011). 2.������� Matern, M. S. et al. GFI1 functions to repress neuronal gene expression in the developing inner ear hair cells. Development 147, (2020). 3.������� Elkon, R. et al. RFX transcription factors are essential for hearing in mice. Nat. Commun. 6, 8549 (2015). 4.������� Milon, B. et al. A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma. Cell Rep. 36, 109758 (2021). 5.������� Hertzano, R. & Elkon, R. High throughput gene expression analysis of the inner ear. Hear. Res. 288, 77�88 (2012). 6.������� Chessum, L. et al. Helios is a key transcriptional regulator of outer hair cell maturation. Nature 563, 696�700 (2018). 7.������� Udagawa, T. et al. Lineage-tracing and translatomic analysis of damage-inducible mitotic cochlear progenitors identifies candidate genes regulating regeneration. PLoS Biol. 19, (2021). 8.������� Elkon, R., Linhart, C., Sharan, R., Shamir, R. & Shiloh, Y. Genome-wide in silico identification of transcriptional regulators controlling the cell cycle in human cells. Genome Res. 13, 773�780 (2003). 9.������� Hait, T. A., Amar, D., Shamir, R. & Elkon, R. FOCS: a novel method for analyzing enhancer and gene activity patterns infers an extensive enhancer-promoter map. Genome Biol. 19, 56 (2018). 10.����� Hait, T. A. et al. The EXPANDER Integrated Platform for Transcriptome Analysis. J. Mol. Biol. 431, 2398�2406 (2019). 11.����� Elkon, R. et al. In silico identification of transcriptional regulators associated with c-Myc. Nucleic Acids Res. 32, 4955�4961 (2004). 12.����� Hait, T. A., Elkon, R. & Shamir, R. CT-FOCS: a novel method for inferring cell type-specific enhancer-promoter maps. Nucleic Acids Res. 50, e55�e55 (2022). 13.����� Shulman, E. D. & Elkon, R. Genetic mapping of developmental trajectories for complex traits and diseases. Comput. Struct. Biotechnol. J. 19, 3458�3469 (2021). 14.����� Levi, H., Elkon, R. & Shamir, R. DOMINO: a network-based active module identification algorithm with reduced rate of false calls. Mol. Syst. Biol. 17, (2021). 15.����� Shulman, E. D. & Elkon, R. Systematic identification of functional SNPs interrupting 3�UTR polyadenylation signals. PLoS Genet. 16, (2020). 16.����� Groenewoud, D., Shye, A. & Elkon, R. Incorporating regulatory interactions into gene-set analyses for GWAS data: A controlled analysis with the MAGMA tool. PLoS Comput. Biol. 18, (2022). 17.����� Levi, H., Rahmanian, N., Elkon, R. & Shamir, R. The DOMINO web-server for active module identification analysis. Bioinformatics 38, 2364�2366 (2022).
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