The three hypotheses driven Projects (P1, P2, P3) have the overarching theme of inflammation/immunity/HIV and are focused, translationally-oriented, and geared to promote extensive crosstalk/synergy among investigators. These proposed studies, that are highly VA-centric, will be conducted at the recently established "Center of Personalized Medicine (CPM)" housed at the STVHCS, and leverage to the fullest extent with the high-throughput capabilities of only one of two genomic facilities in the VA system. These capacities will be tapped into and expanded upon further via funding from the proposed PP and this expanded facility is designated as the Core of this PP. This facility, initially launched at the end of 2009, is fully functional and has been supported by a variety of funds (local VA supports the service costs and the PI of the PPG has expended flexible non-NIH resources available to him to support this facility). We anticipate a high level of scientific and manpower capacity building at STVHCS with national impact because our expanded Core will bolster genetic/epigenetic/genomics studies for the recently established Million Veterans Project. Hence, our Core operates as a central node or focal point of the entire PPG from which all genetic, epigenetic and transcriptomic data emanates from;this facility is fully equipped with contemporary Illumina platforms (recently acquired HiSeq2000 platform) that can cover the entire range of methodologies that are encompassed in contemporary system's biology approach. In our Core diverse techniques such as genome wide association studies (GWAS), transcriptomics analysis by microarrays and RNA-seq, and DNA methylation mapping through beadchip can be readily performed. Given the high level of expertise required to support high-scale genomics and translational research, the Core will tap into the four existing units of the CPM that provide distinct functions: (i) Genomics/Bioinformatics (supported by local VA);(ii) Biostatistics and (iii) Clinical and (iv) Administrative (supported by funds from the University affiliate). The Core will be coordinated by one Director (He), who has extensive experience in molecular biology and genomic research;this individual also has vast experience in handling large data sets, and strong "people skills" to synergistically bring together the different components of the PP. The VA investigators have expended significant energies in expanding bioinformatics/biostatistical capacity as reflected by the preliminary data presented. There is strong VA and UTHSCSA support for the PPG [VA supports Bioinformatics Unit of the Core and service contracts;and UTHSCSA provides administrative support]. The PP enhances collaborative DoD-VA research as it capitalizes on a unique cohort of US Service personnel who acquired HIV infection. This provides the platform for a high degree of synergy as each Program capitalizes on this well characterized ~5000-person cohort with banked prospectively collected biological specimens to address incisive hypotheses related to immune depletion and recovery in the context of untreated and treated HIV infection. Furthermore, the PP will tap into existing collaborations to integrate genomics and transcriptomics data setting the stage for moving from genes to function and predictive medicine. Thus, the specific aims of the PP directly relate to defining genetic/transcriptomic signatures that predict immune recovery on antiretroviral therapy (ART), providing novel targets for therapy. The work we propose will significantly build capacity for genetic/genomic/epigenomic research at our local VA and can be used as a resource for the larger VA research community. We believe that the work proposed through the core will be transformative and provide a platform for VA investigators to conduct cutting edge contemporary research towards advancing Personalized Medicine. Thus, the VA research community and the MVP project can leverage our genomic, epigenomic, transcriptomic and bioinformatic skills and expertise to immensely benefit our patients who are veterans.
The PPG will use state-of-the art technologies and approaches that will identify the mechanisms that underpin questions that are fundamental to our understanding of immune recovery on antiretroviral therapy (ART) and improving the care of our VA patients: Why do some HIV infected individuals manifest immunological alterations and age-associated disease similar to those in elderly individuals despite suppression of viral load by anti-retroviral therapy (ART)? Can we develop laboratory tools that can predict the immunological health in patients on ART? Thus, we anticipate that the results of these studies will define genetic/genomic-based signatures that may predict response to ART. The PPG capitalizes on a long standing partnership between investigators at the VA and those in the DoD by investigating a cohort of active duty, retired or deceased service members infected with HIV. We anticipate these results may identify novel targets for therapies and provide tools to assess immunological health.