Dartmouth College

NIH Research Projects · FY 2025 · 2011-07

OVERALL CORE CENTER PROJECT SUMMARY Digital therapeutics that deliver science-based, behavior change interventions targeting substance use disorders (SUDs) and related issues (including HIV risk behavior and mental health disorders) can markedly improve access to care, quality of care, and treatment outcomes, while reducing costs, for a wide array of audiences in diverse settings. Our interdisciplinary group received a P30 “Center of Excellence” grant from NIDA 9 years ago to launch a new research center (the Center for Technology and Behavioral Health [CTBH]). CTBH has led the field in the development, empirical testing, and implementation of digital therapeutics targeting SUDs and related issues. In this renewal application, we propose to build on this work and grow activities to address the most timely and significant research priorities for the field to: (1) enhance our collaborative work with a wide array of scientific, clinical, industry, and governmental partners to scale access to science-based digital therapeutics across the U.S. and beyond; (2) expand activities to link CTBH’s innovative research in digital health measurement to inform personalized digital therapeutics; (3) accelerate research and mentorship on transdiagnostic digital treatments for substance use and co-occurring mental and physical health conditions (CODs); (4) expand research and resources on digital health ethics and (5) broaden the diversity and inclusiveness of digital health researchers by increasing mentorship and representativeness of underrepresented minorities in digital health research. The Overall Aim of the P30 Center is: To integrate expertise across multiple disciplines and provide an infrastructure to enhance the quality, pace of achievement, and impact of innovative scientific research that combines science-based behavior change interventions with state-of-the-science technologies to create, evaluate, and disseminate digital therapeutics targeting SUDs and co-occurring disorders (CODs). CTBH will achieve this Aim via 5 Cores: (1) The Treatment Development and Evaluation Core will provide resources and training to enhance the quality, efficiency, and impact of research and support mechanisms to accelerate the state-of-the science of digital health assessments and therapeutics (2) The Dissemination and Implementation Core will disseminate research methods and findings and advance a scientific understanding of successful implementation of digital therapeutics in diverse settings, (3) The Emerging Technologies and Data Analytics Core will enhance education and research on the application of emerging technologies and data analytics to digital therapeutics and support shared resources to enhance the pace of development, and potency of, digital therapeutics, (4) The Pilot Core will support the development of new areas of research that could progress to larger-scale testing via external funding after the pilot phase, and (5) The Administrative Core will provide programmatic leadership that ensures successful coordination of activities across Cores and an infrastructure to enhance synergy among our interdisciplinary team.

NIH Research Projects · FY 2025 · 2010-09

Abstract This application for renewal of the grant supporting the New Hampshire IDeA Network of Biological Research Excellence (NH-INBRE) proposes to 1) support engagement of PUI-P students in biomedical research to expand research and career development.; 2) increase success obtaining external biomedical research funding at R15 eligible NH-INBRE institutions; 3) improve statewide data science capabilities, education, and infrastructure; and 4) facilitate collaborations within and outside the NH-INBRE network that support prior aims and biomedical research within and outside NH. The components and organization of the Network are described as is the progress made during the first 14 years. The Geisel School of Medicine at Dartmouth will continue to be the Lead institution and house the NH-INBRE Administrative Core. The University of New Hampshire at Durham will also continue as the Co-Lead institution. The proposed Partner institutions include 8 four-year primarily undergraduate institutions and the Community College System of New Hampshire. NH-INBRE will be led by a team of accomplished faculty, all of whom direct active, federally-funded research laboratories. A team of multiple faculty, administrators and evaluators constitutes the Administrative Core (AC) of NH-INBRE and will be led by Principal Investigator Dr. Steven Fiering. This team-based approach, rather than relying solely on the Principal Investigator and Program Coordinator, has proven effective in establishing NH-INBRE and initiating diverse programs. Different components of NH-INBRE, including Cores and the Developmental Research Projects Program, will collaborate to achieve the goals of NH-INBRE and Internal Independent Evaluation will evaluate all our programs. A wide variety of metrics will be used for ongoing evaluation and improvement of NH-INBRE. The plan is centered on the belief that original scientific research is crucial for scientific training of college students, and expanding the participation of students and faculty at Partner institutions in original scientific research on their campuses is essential for fostering a culture of biomedical research within New Hampshire's institutions of higher education and the state overall.

NIH Research Projects · FY 2024 · 2009-08

PROJECT SUMMARY/ABSTRACT Modern biomedical research relies on new approaches to advance our understanding of complex and multifaceted illnesses of growing public health significance such as cancer. Emerging technologies enable population scientists to generate data on a scale never before imaginable (i.e., through whole genome array scans). Thus, there is a critical need to not only train the next generation of scientists in the classic disciplines involved in studies of human malignancies, but to cross-train them in complementary disciplines to allow them to bring their scientific discoveries to light. Therefore, we propose to continue a highly successful postdoctoral program that combines specialized research knowledge and methodologies in the fields of bioinformatics, biostatistics and epidemiology. This novel program, entitled “Training Program for Quantitative Population Sciences in Cancer,” is structured to complement the existing resources for cancer research and education at the Geisel School of Medicine and the Norris Cotton Cancer Center (NCCC), an NCI designated Comprehensive Cancer Center affiliated with the Geisel School of Medicine at Dartmouth and Dartmouth Hitchcock Medical Center (DHMC). Our training efforts will continue to be led by investigators with complementary expertise in the fields of bioinformatics, biostatistics and epidemiology primarily within the Departments of Biomedical Data Science, Epidemiology and Molecular and Systems Biology. We will capitalize on Dartmouth’s talented cadre faculty in these disciplines who can offer expert mentorship, and a versatile portfolio of research and center grants that can supply access to a wealth of population science data, biologic samples and core research facilities. To accomplish our objectives, we propose to cross-train eight postdoctoral trainees in epidemiology, bioinformatics or biostatistics for a period of 2 to 3 years. Trainees will be paired with a primary and secondary mentor from two of the focus disciplines and complete cross- disciplinary coursework with an optional MS degree in Quantitative Biomedical Sciences. In years two and three of the program, trainees will concentrate on the conduct of mentored research activities, prepare a mock NIH grant application, and participate in the preparation of professional manuscripts, presentations at symposia and scientific conferences and an optional research externship. Program leaders, in consultation with an Advisory Committee, will select trainees, monitor their progress and provide recommendations to ensure that the necessary didactic and research experiences are provided to produce highly knowledgeable investigators for the future of interdisciplinary cancer research in the population sciences. The ultimate goal of the training program is to accelerate cancer research by enhancing the existing pool of cancer researchers with the skills to meet the present and future challenges in translational cancer research in the population sciences.

NIH Research Projects · FY 2025 · 2007-01

Placebo treatments can induce clinically significant benefits across a variety of disorders. These benefits are not due to the treatment itself, which is pharmacologically and physically inert, but to the effects of the interpersonal context and treatment cues on the patient’s brain. This R01 renewal funds an ongoing program of research that has made fundamental contributions to the neuroscience of placebo effects. Neuroscientific studies from our group and others have established that placebo treatments influence cortical-subcortical brain pathways and neurochemical systems related to the endogenous control of pain, threat, and other affective responses. Placebo treatments influence internal conceptual models of the situation and its impact on the self, interacting with learning systems to create stable patterns of affective reactivity. These systems are also central to symptom progression across mental health, substance use, and other brain disorders. Understanding placebo effects will thus help improve psychological and neurological treatments across disorders. Our previous work identifies several significant gaps important for connecting placebo research to mental health. First, not all placebo treatments influence affective brain processes in fundamental ways, and it is critical to identify the factors that underlie deep and durable influences. A key may lie in the nature of the interpersonal interactions involved. In spite of their critical importance, few neuroscientific studies investigate the qualities of the care provider and the provider-recipient match that lead to powerful therapeutic effects. Second, treatments must be studied at a computational level, incorporating models of the dynamic learning processes that create robust and durable effects. Third is a need to investigate brain pathways across multiple types of affect relevant for mental health. In Aim 1 (Studies 1-3), we develop an interpersonal placebo paradigm that allows for the study of provider-recipient resonance. We probe placebo effects across multiple types of affect, including pain, fear, and cognitive performance under threat using fMRI (Study 1), autonomic responses (Studies 1 and 2), and some of the first direct neural recordings of interpersonal influence in humans (Study 3). In Aim 2, we extend this work to consider interactions with the recipient’s mental state. We use fMRI to compare and study the interaction between placebo suggestions and mindful acceptance (Study 4), testing the hypothesis that a state of relaxed, mindful awareness will increase receptivity to placebo suggestions and potentiate placebo effects. Across studies, computational models test whether placebo treatments, and their enhancement by interpersonal processes, influence learning dynamics in a way that creates self-reinforcing effects resistant to extinction.

NIH Research Projects · FY 2025 · 2001-08

Motivated by soaring spending and stagnating life expectancy, the first 20 years of this Program Project Grant (PPG) has focused on the causes and consequences of healthcare efficiency in the U.S. This work has advanced fundamental scientific knowledge regarding sources of inefficiency and has motivated significant changes in healthcare policy and delivery for millions of Americans. This competitive renewal responds to the NIA’s prioritization of Alzheimer’s disease and related dementia (ADRD)-related research by shifting the focus of this PPG to inefficiency in healthcare services and delivery for persons with ADRD. Recent PPG research showed excess mortality among older adults with ADRD, especially for people living in nursing homes. Differences in care delivery for patients with and without ADRD – and between subgroups of patients with ADRD – run the gamut from modifiable risks that contribute to development of ADRD, initial diagnosis and referral, ongoing treatment and support, and throughout later stages, including end-of-life care. Conceptually, the drivers of individual health outcomes will be documented among persons with ADRD from the social ecological perspective which recognizes nested ‘systems’ that interact with one another (individual, interpersonal, organizational, structural, community, and policy). This PPG renewal, therefore, proposes projects focusing on each concentric circle of this model and their interactions. Project 1 will explore state-level policy heterogeneity and its influence on access to home and community-based services for nursing home eligible adults with ADRD. Project 2 will test the hypothesis that having resident service coordinators for adults who live in affordable senior housing decreases adverse health care service use and increases home and community-based service use for low- income residents with ADRD. Project 3 will explore trends in the quality of primary care for people with ADRD and to identify modifiable policy-, system- and practice-level factors that contribute to better outcomes. Finally, Project 4 will develop a novel measure of provider diagnostic test ordering in the acute care setting and explore the impact of diagnosis on the trajectory of patients with ADRD. Projects achieve synergy by using the social ecological model to examine how interactions among the key variables examined in each project could operate together to improve outcomes and reduce healthcare inefficiency, and by relying on shared administrative, data and analysis, and methodology cores.

NIH Research Projects · FY 2025 · 1997-09

This application requests support to continue the Host-Microbe Interactions (HMI) Predoctoral Training Program which is an interdisciplinary training program that seeks to provide research and curricular-based training to a pool of talented and highly motivated students who seek training in microbial pathogenesis and beneficial host-microbe interactions. The HMI program consists of 18 Training Faculty who have an average of $736,699 direct costs per year, and annual direct costs for research total to $13.3 million. Trainers currently have 72 trainees in their labs. Areas of strength among our Trainers include molecular genetics of bacterial, fungal, and viral pathogenesis, and prion biology, study of the microbiome, interaction with immune and epithelial cells, and ecological modeling. These areas are pursued using the full range of modern genetic, molecular, biochemical, immunologic, and computational techniques. Trainees are supported by one of three excellent multidisciplinary graduate programs, the Microbiology and Molecular Pathogenesis program (M2P2), and the Guarini School of Graduate and Advanced Studies. We have both hired new faculty whose research is directly aligned with the program goals, indicating the institution’s commitment to research in microbiology and recruited to our program Dartmouth faculty whose research in host-microbe interactions has expanded. Most importantly, our past Trainees have been extremely successful. Of the 33 HMI Training Program Trainees who have left Dartmouth in the past 15 years, 32 are in PhD-level careers in science and one is a high school science teacher and thus is still leveraging their training. HMI Trainees from the past ten years have published 83 papers. In the past four years since the last renewal, we have made several positive changes to the program including 1) mentor training from the Center for the Improvement of the Mentored Experiences in Research (CIMER) with 94% of our Trainers having already completed training, 2) increased the involvement of early career or new-to-Dartmouth faculty in program subcommittees, 3) enhanced support for preparation of F31 applications, and 4) focus of a Trainee curriculum that is broadly useful across sub-disciplines within the area of host-microbe interactions. To continue our positive impact on the biomedical workforce, we request to continue supporting five trainees per year.

NIH Research Projects · FY 2025 · 1997-08

As the only NCI-designated Comprehensive Cancer not located in a major urban hub, the Dartmouth Cancer Center (DCC) oversees all cancer-related academic and clinical activities across both Dartmouth College and Dartmouth Health. We are committed to providing high-quality clinical care and generating important new knowledge benefiting cancer patients in both our rural, two-state catchment area and around the world. DCC delivers nationally recognized, compassionate, community-based care to its catchment area, supporting cancer health and validating new models for optimizing rural cancer care delivery and prevention. Drawing on cancer research talent from across a world-class liberal arts college, medical school, graduate school, engineering school, business school, and academic health system, DCC’s mission is to accelerate trans-disciplinary research to prevent and cure cancer, enhance survivorship, promote cancer-related health, and train the oncology workforce for the future. DCC has four trans-disciplinary Research Programs: 1) Cancer Population Sciences (CPS), 2) Translational Engineering in Cancer (TEC), 3) Immunology and Cancer Immunotherapy (ICI) and 4) Cancer Signaling, Genomes, and Networks (SGN). These programs provide oversight of robust, program- specific clinical trial portfolios and generate therapeutic innovation, high-impact publications, and extramural funding. Their growth in the past funding cycle includes a 23% increase in cancer-relevant, peer-reviewed funding and a doubling in the number of multi-component/multi-PI awards. DCC researchers produced impactful interdisciplinary and translational discoveries, including multiple publications on rural cancer health, and formed a new Center for Rural Health Care Delivery Science. During the most recent funding period, DCC recruited 56 new junior and senior faculty members spanning 19 departments across Dartmouth’s Geisel School of Medicine, Thayer School of Engineering, College of Arts and Sciences, and Dartmouth Health. Since its last NCI renewal, DCC has: 1) delivered nationally-recognized Press Ganey “Pinnacle of Excellence” award-winning cancer care to close to 100,000 individual patients across a now fully integrated Oncology Service Line; 2) accrued more than 6,000 patients to interventional clinical trials; and 3) doubled patient accrual to both therapeutic clinical trials and to NCTN Lead Academic Participating Site target accruals. DCC has additionally expanded its Cancer Research Training and Education Coordination (CRTEC) and Community Outreach and Engagement (COE) efforts, charged with generating synergies across DCC’s Research Programs to reduce the multiple burdens of cancer. The efforts are a vital part of DCC’s 2023 Strategic Plan, which provides a roadmap for starting DCC’s second half-century dedicated to improving the lives of cancer patients and promoting cancer health.

NIH Research Projects · FY 2025 · 1992-01

In adults, herpes simplex virus (HSV) causes ocular diseases ranging from mild to sight-threatening. In addition, HSV causes cold sores, genital sores, encephalitis, and is implicated in the genesis of neurodegenerative disease and Alzheimer’s. The lifecycle of HSV comprises an acute infection at mucosal sites (e.g. the cornea) when all virus genes are expressed, and latency in neurons, when viral gene expression is limited. Most clinical and preclinical studies of HSV use adults in both humans and animal models. Neonatal HSV (nHSV) infections, however, result in traumatic manifestations and occur following exposure to HSV-1 or HSV-2 either during parturition or the early postnatal period. Infected newborns develop skin, eye, and mouth (SEM) disease, or disseminated infections and encephalitis. Without treatment, mortality is high (≤ 57%), largely due to difficulties diagnosing nHSV which is often mistaken for sepsis. Surviving infants develop long-term sequelae including anterior and posterior segment ocular disorders, neurodevelopmental disabilities, blindness, spastic quadriplegia, and seizures, incurring significant emotional and economic burden. Acyclovir (ACV) is the standard of care, but initiation of ACV therapy requires clinical suspicion. Even aggressive ACV treatment of generalized nHSV infection leaves ~70% with neurosensory and ophthalmic sequelae. It is imperative, therefore, to develop new options for prevention and treatment of nHSV in this vulnerable, and understudied population. nHSV transmission and risk patterns are counterintuitive. HSV vertical transmission risk is lowest (<1% of cases) from mothers with long-standing pre-existing genital infections, even with proven recurrence during birth. >85% of cases arise from a primary maternal infection during birth, and ~15% of cases follow postnatal infection from the community following birth to a seronegative mother. This risk pattern is consistent with the hypothesis that protection is conferred through transfer of maternal antibodies. These antibodies cross the placenta and supplement the underdeveloped fetal and neonatal immune system to protect against congenital infections. These antibodies also pass in the breast milk. We have shown that maternal antibodies access fetal and neonatal neural tissues with surprising efficiency and prevent nHSV in mice. We have developed a novel mouse model wherein we study not only morbidity, mortality and viral burden, but also behavioral pathologies (testing vision, anxiety, learning and memory) observed in humans following nHSV. Our overarching goal, is to explore use of an experimental vaccine (dl5-29), and a therapeutic monoclonal antibody (mAb) (CH42) expressed by an AAV vector to prevent damage to the visual system and CNS following nHSV. Our data also implicate a role for perturbation of the autophagy pathway in the development of corneal and CNS diseases and we will assess how novel autophagy-modulating therapeutics may ameliorate the sequelae of nHSV. Overall, these translational studies will study an area problem of high clinical significance — the development novel interventions targeted to improve neonatal health outcomes following HSV infections.

NIH Research Projects · FY 2025 · 1990-09

This proposal aims to continue to improve the quality and breadth of predoctoral immunology training at Dartmouth. It builds upon and improves a continually funded T32 program that has been successfully training the next generation of immunologists for thirty years. The scientific focus is to better understand the immune system in health and disease and to leverage these findings to develop better therapies for an array of different conditions where the immune response is central to pathogenesis. Our goal is to provide a cutting-edge program to train the best graduate students to conduct rigorous and ethical research in the field of immunology. Trainees will be mentored to become productive researchers who are experts in their fields and also very well-informed about immunology as whole. Faculty trainers are drawn from a wide variety of areas within immunology. The program can therefore offer interdisciplinary training that includes the interfaces between immunology and infectious disease, cancer, mucosal homeostasis, pulmonary disease, autoimmunity and systems biology. In addition to training in the design, implementation, reproducibility and interpretation of research projects, the program teaches students how to effectively present their research in seminar presentations and in written formats such as grant proposals. Major strengths of the program include: (i) the strength of the research programs of the training faculty. Faculty research program represent a broad array of disciplines within immunology, many of which span different fields and involve interdisciplinary collaborations with different labs both within Dartmouth and at other institutions. The relatively small size of Dartmouth laboratories also leads to very close interactions between faculty and trainees, creating an ideal learning environment. (ii) Students appointed to the training program enter through two very strong umbrella graduate programs, the Molecular and Cellular Biology program and the Quantitative Biological Sciences program. Graduate education is coordinated by the Guarini School of Graduate and Advanced Studies, that offers a wealth of professional development activities for students, supplemented by activities by training program trainers, to help them with their future careers. (iii) The Geisel School of Medicine and Thayer School of Engineering at Dartmouth offer state-of-the- art facilities for laboratory research, computational and statistical resources, an AAALAC approved animal facility and core facilities for genomics and bioinformatics. In this competitive renewal we detail new training programs that have been added during the last grant period and new initiatives we propose adding to the training program. The Dartmouth Immunology Program has had outstanding track record of success in training young immunologists over the past thirty years, and trainees populate many of the most prominent immunology laboratories throughout the world. We will augment this success in the current proposal and train scientists who will become the future of immunology research.