Principal Investigator:

Contributors: Aleksandar Milosavljevic, Mark Bender Gerstein

DESCRIPTION (provided by applicant): Advanced genetic and genomic technologies promise to transform our understanding and approach to human health and disease. Such genomic analyses are now common in Western populations of European descent. Studies of host genetic factors underlying long-term non-progressors of HIV infection have led to new therapies through the identification of loci that are important to in vivo control of virus pathogenicity. Similar studies of host genetic factors influencing active TB infection have also identified important loci that could significantly impact the future development of more effective therapeutic and prophylactic strategies. Most of these studies were undertaken in non-African, adult populations, although there are more than 2 million new cases of HIV and HIV-TB in Sub-Saharan Africa every year, including more than half a million in children. HIV-infected children – who differ from their adult counterparts in their route of acquisition, clinical course, and pathophysiology – have been conspicuously absent, although they potentially have more to ultimately contribute and gain from therapeutic advances. The Collaborative African Genomics Network (CAfGEN) aims to redress this scientific imbalance by integrating genetic and genomics technologies to probe host factors that are important to the progression of HIV and HIV-TB infection in sub-Saharan African children. The network will incorporate five sites – the Botswana and the Uganda Children’s Clinical Centers of Excellence will provide clinical expertise for patient recruitment; Makerere University and the University of Botswana will provide local molecular genetic expertise; and Baylor College of Medicine will provide access to genomics expertise and resources that will ultimately be transitioned to African researchers and institutions in a sustainable manner. The CAfGEN research agenda includes the recruitment of prospective and retrospective cohorts of HIV and HIV-TB infected children; the development of core genomic facilities for sample processing and storage; candidate gene re-sequencing, HLA allelotyping and whole-exome sequencing of patients at the extremes of HIV disease progression; and integrated genomic analyses of active TB progression and associated clinical outcomes using expression quantitative trait loci. These projects will be undertaken through an extensive training and career development plan that will also see significant upgrades in local genomics infrastructure, in so doing, CAfGEN will create a unique, highly synergistic African alliance that can contribute novel and important mechanistic insights to pediatric HIV and HIV-TB disease progression while establishing sustainable genomics technology, expertise, and capacity on the African continent.

The DMRR SOC will 1. provide the scientific community with user-friendly, publicly accessible ExRNA information, and 2. make the scientific community aware that this information is available for their use.  Anticipated activities of the DMRR SOC include:

1. Establish and maintain a public website which will include an ExRNA Atlas.

  • The Atlas will describe subcellular production pathways, tissues of origin, principle binding partners and/or cofactors, principle cargo constituents, and potential cellular or pathway targets of specific ExRNA populations from “normal” human body fluids.
  • Included in the Atlas will be an “E-Manual” of validated and standardized Extracellular RNA protocols (isolation, manipulation, RNA-seq, etc) to be updated as protocols and technologies improve.
  • The Atlas will contain information about common reagents, useful separation biomarkers, quality control standards, standard cell line/producer line, gold standard reagents, etc to ensure lab-to-lab consistency in ExRNA preparations.
  • The Atlas should provide access to videos and tutorials (generated by the DMRR in collaboration with the ERCP PIs) on ExRNA biology, the use of ExRNA datasets and protocols, and related issues to help educate the scientific and lay community on these topics.
  • The Atlas should provide user-friendly access to datasets generated by the consortium, provide ExRNA profiles/signatures of healthy individuals, provide access to ExRNA biomarker datasets, and provide access to other relevant available datasets generated by non-consortium researchers.
  • The Atlas will be the primary portal for the broad scientific community to access ERCP data prior to publication and should provide access to “apps” as well as more sophisticated tools to facilitate data mining by both novice and experienced researchers.  The Atlas should provide access to useful software developed by the ERCP Consortium and other researchers.
  • The Atlas should describe all of the datasets available for the ERCP and have metadata-enabled querying of the data to identify data subsets of interest.  Links should be provided to a description of the data including any metadata associated with an experiment.  The Atlas should provide a method to freely download large datasets so that users can acquire and analyze all or large parts of the data.  The Atlas should support data retrieval for any ERCP data deposited in NCBI or other public databases.
  • The Atlas should provide a genome browser view of the ExRNA data generated by the ERCP Consortium, and should strive to make the visualization of the data as intuitive and user-friendly as possible.
  • The Atlas should improve during the course of the project.  Applicants should describe plans to solicit user feedback and otherwise evaluate the usability of the Atlas that serve the user communities, as well as to facilitate analysis of usage (quantitation of page views, FTP downloads, etc.).   This plan should describe the frequency of these evaluations and how this information will be used to improve the utility of the Extracellular RNA Atlas to the user community.

2. Develop an outreach strategy to advertise available ERCP protocols and resources to the scientific community.  The outreach strategy should include:

  • sponsorship of workshops open to scientists outside of the consortium to facilitate use of datasets.
  • support of sessions at scientific meetings to advertise ERCP discoveries and resources.
  • establishment of a discussion forum to engage the scientific community interested in this topic.
  • utilization of appropriate social media outlets for information about ERCP.

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