CTSI Annual Pilot Awards to Improve the Conduct of Research

An Open Proposal Opportunity

Improving Capacity for Translational Research in Tuberculosis

Proposal Status: 

Rationale: The purpose of this application is to strengthen the tuberculosis (TB) translational research capacity at UCSF/SFGH by developing a BSL-3 laboratory in which work with human TB can be safely carried out in tissue culture and in small animal models.  Such work will enable us to extend observations that we have made in molecular epidemiological studies of TB in San Francisco, permit new lab-based investigation in the context of existing, funded clinical studies in San Francisco and abroad, and facilitate additional studies in animal models of infection. Having such a facility will enable us to examine immunological responses to as well as the pathogenicity and virulence of clinical strains of M. tuberculosis (M.tb) isolated from patients in San Francisco and in other areas across the US and globally, and to study the impact of co-infections with M.tb and other pathogens (e.g., HIV). We have a superb multidisciplinary group of investigators working in the US as well as in Kenya, Tanzania, Zimbabwe, Uganda, and Vietnam in studies of the transmission and pathogenesis of TB. In a number of these studies, observations have been made that suggest differences among strains and interactions between specific strains and hosts of specific race/ethnicity. Examination of these findings in lab-based studies and/or in an animal model will, if confirmed, enable back translation to human studies and approaches to vaccine and drug development. The availability of a new BSL-3 will facilitate the work of investigators working across many disciplines and enable questions to be addressed that can only be examined in animal models. Given the international scope of existing research activities, this effort will also mesh with efforts at UCSF and SFGH to enhance global health. In recent efforts to recruit an investigator focused on TB immunology, the major limiting factor has been the lack of BSL-3 space. Thus, having such a facility is a critical element in filling a critical deficiency in our TB research program.

Plan: Although a BSL-3 laboratory exists in Building 100 at SFGH, this laboratory is heavily utilized, inadequately designed, and not amenable to the maintenance of M. tb infected animals. Other alternatives have been carefully explored but deemed not feasible for reasons of experimental protocol, safety, and/or cost. We propose to upgrade an existing BSL-2 laboratory in Building 3, a seismically sound building, to BSL-3 status. Based on input from the construction firm that built the existing space, the total cost of the build-out of the BSL3 is estimated to be $1.2M. There is widespread enthusiasm and broad support to create such a facility, as indicated by commitments that total $950,000 from a consortium of funders including the Department of Medicine, the Medical Service at SFGH, the SFGH Dean's Office, and the Ireland Fund, but there remains a $250,000 deficit. We are asking for $100,000 to help leverage these commitments. Given our success in raising the needed funds, we are confident that the additional $150,000 will be secured, even if it means obtaining a loan that would be paid back by users over time.

Criteria and Metrics for Success: The single metric will be the hiring of one independent TB immunology investigator by 2013. The Division of Experimental Medicine will commit the resources for at least one start-up package to hire faculty members focused on the immunology of human TB. Each package would include at least $1M in start-up funds and the provision of BSL1 and BSL2 space ensuring that, if the BSL-3 is built, the criterion of success will be met.

Approximate Cost and Justification: We are requesting $100,000, an amount that will be combined with additional resources that have already been committed (see above). These aggregated funds will be used to purchase or construct: 1) animal holding space with self-contained cage ventilated racks for mice or guinea pigs; 2) several biosafety cabinets for the safe handling of M.tb in tissue culture; 3) autoclave alcove to house the autoclave and the CO2 gas manifold; 4) clean vestibule (entrance and exit); 5) dirty vestibule (entrance to both of the laboratories and the animal holding room); and 6) ultralow freezer for storage of bacterial stocks and infected tissues. The space will have the mechanical system required for a completely independent ventilation system.

Faculty who would use this facility: Hopewell, Havlir, Kato-Maeda, Catamanchi, Davis, Metcalfe, Nahid, Everett, Cox, McCune, Nixon


It's surprising to hear that the TB research at SFGH is happening in marginally adequate facilities. San Francisco has the highest incidence of TB of any city in the United States, and most of these cases are seen and treated at SFGH. Given the power of animal models and the increasing attention being paid to human immunology by the NIH, it seems that having a state-of-the-art facility at such a location would be a good investment in UCSF and San Francisco's futures.

The tuberculosis researchers at San Francisco General Hospital have worldwide renown. SFGH has a tremendous history of providing care for patients with tuberculosis and advancing knowledge in treatment, prevention, diagnosis, and epidemiology. As the Hospital Epidemiologist and an infectious diseases physician at SFGH, I am keenly interested in seeing tuberculosis research at SFGH proceed in an appropriate setting as described in the proposal.

SFGH and its infectious disease researchers and clinicians create a key and unique interdisciplinary team capable of making SFGH a leader in TB research. The addition of a new BSL-3 facility will not only expand the available space to work with this serious public health threat, but will enable basic research using small animals. The inclusion of TB basic research in small animals is necessary to recruit TB basic immunologists and will without a doubt expand the role of SFGH in basic and clinical TB research.

This is an incredibly important resource for the SFGH/UCSF research community.

This would support a still growing community of TB investigation and could be helpful in recruiting new faculty members as well. Are there any facilities that approach BSL3 level containment at any of the other campus sites? I suspect not and if that's true, could investigators not located at SFGH collaborate in work in this new space? And help support it?

The establishment of a BSL3 facility for TB research would be a fantastic and logical addition to the existing human immunology infrastructure at SFGH and would help to bridge the gap between translational scientists and the excellent clinical TB researchers at SFGH. Several SFGH researchers have established valuable international cohort studies that are ripe for immunologic collaborations. Such a facility would extend UCSF's existing strengths in human translational immunology and plug a major hole in our research infrastructure, by enabling tissue culture and small animal model studies of TB. This facility would be used by many existing UCSF faculty and its creation would also be a critical step in facilitating recruitment of a faculty member with expertise in human TB immunology.

A much needed BSL3 that will strengthen and add new dimension to TB research. CTI participation in this endeavor will leverage the already committed money for clinical and translational investigation.

I am a junior faculty member involved in human studies of tuberculosis. In particular, many of my studies are focused on development and validation of immune-based diagnostics. A new BSL-3 facility to support animal studies would help: 1) recruit a world-class TB immunologist to UCSF/SFGH 2) test hypotheses generated from human studies in animal models and vice versa Both of these factors are critical to the future success of TB-related research at SFGH, and would directly benefit the ongoing studies of a number of faculty members.

I was disappointed to learn that despite the presence of TB experts and significant TB research being conducted at SFGH, there is no BLS-3 laboratory for TB research. This award will be a valuable first step towards addressing this glaring deficiency.

The history of TB is intertwined with that of San Francisco General Hospital and there is a strong core of researchers studying TB who are based at SFGH. The establishment of a BSL-3 facility at SFGH would expand the research capacity at SFGH and would help attract additional scientists and grant funding.

UCSF is internationally recognized as one of the top academic centers with expertise in TB management, education and research. Moreover, the pool of TB researchers at UCSF and SFGH is perhaps only paralleled by the group at Hopkins. Not having a BSL3 at SFGH is a major hindrance to the university's ability to expand TB and HIV/TB related activities. I would anticipate that the cost of a BSL3 will more than adequately be covered by the many extramural funds that the group would be able to successfully compete for.

It is surprising that SFGH, which is positioned at a convergence of clinical and academic research, currently lacks the facilities to perform such experimentation. The limitations of the building 100 BSL-3 create an unnecessary bottleneck for tuberculosis research that forces an excessive dependence upon outside sources to complete experiments. This investment will both alleviate a weakness and reinforce UCSF’s and SFGH’s prominence as premier institutions for tuberculosis management by providing the necessary tools to remain competitive and attract world class researchers and clinicians.

The new BSL3 facility will overcome a critical obstacle to building the Mtb program at SFGH and UCSF. As Chief of the Pulmonary Division at SFGH, I can attest to years of inability to recruit a TB immunologist, mainly due to the inability to study Mtb-infected mice. Now, a high level recruitment is in process, only dependent on solving this problem. Much of the money has been secured and this $100k would be a key final investment.

As a junior faculty member focused on clinical-translational work in tuberculosis (TB), I offer a strong endorsement of the stated needs for a well-equipped BSL-3 facility to allow UCSF to expand its capabilities in TB research. My current nascent studies of MTB host-pathogen interactions in vivo would greatly benefit from enhanced local expertise and interest in studying these interactions in model systems, research that is infeasible without the prooposed facility. TB affects 3 billion people worldwide, yet the understanding of the complex immunology related to this infection remains rudimentary. Having the facilities at UCSF to carry-out experiments to understand this process is critical to advancing our knowledge of this area, so that we can design new and better diagnostics, drugs, and vaccines.

I agree with my coolleagues comments above. I wish to add that I have plans to collaborate with another UCSF colleague that studies TB, and our work would greatly benefit from having more accessible facilities. I am very hopeful that these facilities become available, especially given all of the multidisciplinary research that could benefit from these.

Tuberculosis remains a major global health problem; one of the components of the global Stop TB Strategy is research including new diagnostics, drugs and vaccines. This CTSI proposal would help strengthen UCSF researchers' capacity to contribute new knowledge to address this ancient disease.

This is a very important proposal for enhancing research in lung disease and global health at UCSF. There is a growing community of scientists studying tuberculosis at San Francisco General with the potential to recruit another senior international leader in this field. There is also great potential to tap into the growing strength on the campus in translational infectious disease research. Currently, scientists at SFGH are severely limited by the absence of an accessible BSL3 facility. There is broad support for this proposal from pulmonary scientists at UCSF. Funding from the CTSI now would be critical for raising the last increment of funding needed to get this project completed.

I am a junior faculty member in the Division of Pulmonary and Critical Care Medicine and undertake clinical and translational research focused on transmission and pathogenesis of M.tuberculosis. A safe, improved BSL-3 facility to undertake sophisticated M.tuberculosis research will be critical in strengthening our current capacity to carry out cutting edge research. In addition, such a facility would greatly reinforce our ability to recruit important faculty, such as an immunologist working at the human-M.tuberculosis interface. This proposal has my complete support.

This is an important proposal and if funded would address a major infrastructure and resource need at SFGH and UCSF. The global phylogenetic diversity of MTB was recognized in large part as a result of population-based molecular epidemiology and genotyping studies conducted at UCSF/SFGH. The implications of MTB strain diversity for global health such as for transmission, pathogenesis, treatment response, diagnostics, vaccine efficacy etc are largely unknown. With an adequate BSL3 at SFGH and with local collaborators, we would be able to augment our population-based studies by evaluating the relevant host-pathogen interactions involved. Until then, the only way we can move this important TB research agenda forward is to seek collaborations with investigators at other universities where adequate facilities exist (OHSU, Hopkins, Berkeley, Stanford), asking them to consider conducting research that we should be doing at SFGH.

Availability of the BSL3 has been critical in allowing me to pursue TB diagnostics research here at SFGH. The clinical laboratory does not have the space nor ability to support the kind of work that I am doing. It has been incredibly helpful to have the BSL3 available and continued availability will be a key part of sustaining active and cutting edge TB research at SFGH.

UCSF and SFGH have established themselves as leaders in the field of TB research. Investment in infrastructure like this lab is absolutely critical for UCSF to maintain its position in this field.

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