Palo Alto Veterans Institute for Research (PAVIR)

Targeted Strategies to Accelerate Evidence-Based Psychotherapy (EBP) Implementation in Military. Principal Investigators: Craig S. Rosen, Ph.D. and Carmen P. McLean, Ph.D. This four-year study, funded by the Department of Defense, is aimed at increasing use of evidence-based psychotherapies (therapies proven effective in research) in clinics on military bases. Despite efforts to train military providers in effective psychotherapies for posttraumatic stress disorder (PTSD), only a minority of service members receive these treatments. This trial tests whether a tailored process improvement approach (using a toolkit for matching specific change strategies to local barriers) is more effective than provider training alone in expanding the proportion of patients who receive an EBP. The project, led by investigators at the National Center for PTSD and Palo Alto Veterans Institute for Research (PAVIR), includes collaborators from five universities and eight military treatment facilities. Objectives: To test in a stepped-wedge randomized trial whether the Targeted Assessment and Context-Tailored Implementation of Change Strategies (TACTICS) increases use of evidence-based psychotherapy more than does provider training alone. Secondary outcomes include effects of TACTICS on average improvement in PTSD symptoms, and satisfaction with the TACTICS process. Accomplishments: All staff have been hired, eight military clinics representing all service branches were recruited and all regulatory approvals obtained. Provider training and clinic-tailored process improvement intervention to increase PE use has been implemented at all eight study sites. Provider survey data collection is completed. Barriers to implementing PE in the military health system and recommended policy level changes to address these barriers have been identified. Centralized extraction of study data and analysis in collaboration with the Defense Health Agency is ongoing. Potential Impact: If effective, TACTICS may represent a scalable approach to accelerating the use of behavioral health best practices in military settings.

Targeting Cerebrovascular TGF Signaling in Alzheimer's Disease. Principal Investigator: Jian Luo Ph.D.Alzheimer's disease (AD) is the most common type of dementia, afflicting millions of victims worldwide, but has thus far proven incurable. With an aging population, this devastating disease will become more widespread in the near future, making the search for effective treatments a principal objective. While the etiology of AD is poorly understood, recent studies indicate that neurovascular dysfunction is an integral part of AD. The transforming growth factor beta (TGF-beta) is a key molecular factor involved in cerebrovascular dysfunction and in various pathological aspects of AD. The objectives of this project are: 1) to characterize changes of TGF-beta signaling in brain endothelial cells during aging and in mouse models of AD. 2) determine the functional effects of modulating TGF-beta signaling in these models, using a novel small molecule TGF-beta pathway activator and other unique tools developed by our labs. Major accomplishments:1) Developed genetic mouse models and viral approaches to study TGF-beta signaling specifically in brain endothelial cells.2) Demonstrated that loss of TGF-beta signaling specifically in brain endothelial cells impairs endothelial and neurovascular function, while activation of TGF-beta signaling in brain endothelial cells improves neurovascular function and attenuates brain pathology in aging and in mouse models of AD.3) Further developed Compound 381 (C381), a novel small molecule TGF-beta pathway activator.4) Performed an "overdose" CRISPRi Screen and identified factors associated with lysosomal acidification and autophagy as the potential molecular target of C381.5) Demonstrated that C381 increases lysosomal proteolysis and protects lysosomes from LLOME damage.6) Demonstrated that C381 improves cognition and reduces pathology in APP751LonSwe-transgenic mice, a mouse model of AD.7) Developed a vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the mouse and human brain. 8) Identified brain-region- and species-enriched genes and pathways in human AD brains and in mouse models of AD. This work not only shows that TGF-beta signaling is reduced in brain endothelial cells in human AD brains and in Alzheimer model mice, but also uncovers the molecular basis of the human and mouse brain vasculature, which will inform our understanding of AD and therapy.Potential impacts:The main findings from this project demonstrate that the loss of TGF-beta signaling during aging and Alzheimer's disease impairs endothelial and neurovascular function, contributing to disease pathology, and importantly, reversing this loss in signaling has therapeutic potential. They will open new avenues in therapeutic development, as well as improve our mechanistic knowledge of this complex and poorly understood disease.Excitingly, our work has produced a promising drug candidate for the treatment of neurodegenerative diseases. We developed C381, a first-in-class compound capable of activating TGF-beta signaling and restoring lysosomal function. C381 has the potential both as a therapeutic and as a research compound to better understand TGF-beta signaling and lysosomal function. Of note, all IND-enabling (Investigational New Drug Application) toxicology studies for C381 have been completed, showing no major concerns. It is our hope to push C381 into clinical trials in the near future, where it can serve as a first-in-class drug for neurodegenerative conditions with lysosomal pathology and help pave the way for other molecules of its kind.

All of Us Research Program. Principal investigators: Philip Tsao, Ph.D. and Jennifer Lee, M.D., Ph.D.The All of Us Research Program (All of Us) is a large collaborative initiative sponsored by the National Institutes of Health (NIH). All of Us includes a consortium of awardees from multiple institutions, including the Department of Veterans Affairs. All of Us is working to improve healthcare through research by building a diverse database of participant self-report information, biospecimens, and Electronic Health Records that can inform future research on a variety of health conditions. VA participation in All of Us is overseen by three Co-PIs, located at the VA Palo Alto Healthcare System and the VA Boston Healthcare System. These two institutions serve as the Coordinating Centers for all participating VA sites, providing leadership and oversight. There are currently 15 VA sites, with plans to add additional sites in the upcoming years. All centralized recruitment, engagement campaigns, and compliance with program requirements is managed by the VA PIs and their respective Coordinating Center teams.

PAVIR is privileged to work with a large community of uniquely talented medical researchers across a broad spectrum of research areas as we fulfill our mission of advancing Veterans and public health through innovative research. The range of research activities is broad and includes special emphasis on major disease categories, all of which are prevalent in the VA's patient population. These include cardiovascular medicine, mental health, chronic inflammatory disease, stem cell/regenerative medicine, pain, sleep disorders, and many others. In addition to disease specific research, PAVIR is engaged in supporting research aimed at enhancing health care. PAVIR's research portfolio includes comparative studies in which research teams are learning which treatments are superior to others, how to augment or improve standard of care, as well as how to enhance the operation of health care. Furthermore, PAVIR is supporting educational activities, especially in areas of advancing clinical care for Veterans and fostering the professional development of our expert staff.