Michael Frank - US grants

Duke University proposes to establish a Center for the Study of Developmental Immunology and Host Defenses. Disorders of immunity play a major role in many diseases of children, with infectious disease being the most prominent example. During normal host defense against infec- tion, damage-producing elements of the response may impact on normal tissue function. Disorders of immunoregulation are associated with the development of autoimmune and allergic diseases. Genetic diseases of almost all of the components of the host defense system have been described. The Center will have a number of components. Overall direction will be provided by the Chairman of the Department of Pediatrics, Michael M. Frank, M.D., a recognized expert in the area of mediators of tissue damage, who will act as Principal Investigator. Direct day to day supervision will be provided by Rebecca Buckley, a leading pediatric cellular immunologist. A major component of the Center will be a core laboratory which will be directed by Louise Markert, M.D., Ph.D., a molecular biologist with demonstrated expertise in the area of lymphocyte development and control and by Dr. Buckley. The core laboratory will be supplied and equipped for studies using molecular biological, chemical and cellular techniques. This core facility will allow for both training and a portion of the research of the junior faculty investigators supported by this program. These pediatricians will all be within three years of completing their training. It is intended that one more advanced junior faculty investigator be singled out for more support and a greater measure of independence. Part of the Center proposal involves identification and recruitment of suitable potential pediatric investigators. One pool of candidates resides in the participants in the Duke residency and fellowship programs, the majority of whom enter academic pediatrics. Techniques have also been developed to identify and attract individuals not currently part of the Duke program, including minority candidates. The program for successful candidates includes training in a broad array of scientific areas that are part of the immunologic and host defense process. These junior investigators will spend two to three years in the laboratory of well known and established investigators in the Duke community who work in this general area. In this role, they will become trained in the basic science of their field. The purpose of the program is to develop independent young clinical scientists in this field who can then gain academic appointments and independent laboratory support at Duke or elsewhere. An assurance of such an appointment will be a powerful inducement for entering academic pediatrics in this area, where there is currently a very great need nationwide.

The overall objective is to elucidate the role of complement in the pathogenesis of xenograft rejection. It is well established that complement activation plays a key role in hyperacute xenograft rejection and its believed that the mechanism of damage of pig xenograft in primates is mediated by natural antibody and the classical complement pathway. Xenografts that survive hyperacute rejection may be destroyed some days later by a process termed acute vascular rejection. The histology of acute vascular rejection is identical to that of hyperacute rejection and we hypothesize that cobra venom factor does not complement components activated by the CVF in small amounts to the graft. This project uses novel complement inhibition and inactivation to prevent complement binding to graft endothelium, studies the effect of complement binding in endothelial cell activation, and examines the binding of immunologically active materials to the graft in such a way as to inhibit or delay acute vascular rejection. These experiments represent an approach to acute vascular rejection using more extensive complement inhibition incorporating agents which activate and inhibit complement. The second aim is to elucidate the mechanism by which antibody and complement binding to grafts initiate graft rejection. The effect of binding of complement proteins to endothelial monolayers and generation of complement activation products will be examined. Cytokine production will be monitored as to explore how complement binding and endothelial cell activation proceed. Finally, the process of accommodation will be examined. The interaction of grafts with antibody and complement under some circumstances appears to protect graft from further damage in several experimental models. The mechanism of this effect will be explored with particular emphasis on the binding of complement degradation fragments to critical graft sits in such a way that the binding of further active complement products is inhibited.

This application proposes a programmatic effort aimed at elucidating the immunological barrier to cardiac xenotransplantation and the development of strategies to overcome that barrier. The rationale for this effort is a very critical shortage of human organs available for allotransplantation. The immunological hurdles include hyperacute rejection in unmodified recipients and acute vascular rejection in xenograft recipients who have been unmodified recipients and acute vascular rejection in xenograft recipients who have been depleted of anti-donor antibodies and/or complement. Other hurdles involve graft injury mediated by neutrophils, natural killer cells and lymphocytes. The program uses a preclinical model involving the transplantation of porcine hearts into the cynomolgus monkeys. The contribution to the rejection process of natural antibodies, complement, and inflammatory cells as well as of reperfusion injury, will be addressed. One central theme of the program focuses on endothelial cells as a target of oxidant injury and in humoral and cell mediated responses as an effector system. Another central theme focuses on the acquired resistance of vascularized organ grafts to humoral mediated injury; test the mechanisms which may contribute to this "accommodated" state. Project 1 considers the contribution of oxidant mediated injury of humoral mediated rejection. Project 2 considers the role of natural antibodies and Project 3 considers the role of complement in this process. Project 4 investigates endothelial cell responses to humoral injury. Project 5 explores the contribution of neutrophils to acute vascular rejection. Projects 6 and 7 investigate how natural killer cells and T-lymphocytes, respectively might interact with a xenogeneic organ. Project 8 studies the pathogenesis and potential treatment of humoral rejection in the large animal model. The overall effort of the program is supported by an administrative core and a cell culture and immunopathology core.

DESCRIPTION (provided by applicant): The lack of understanding of the processes underlying pediatric illnesses and their appropriate therapy inflicts a heavy burden on children and their families. Our program will address this issue by selecting, training, mentoring, and placing young pediatric investigators in the areas of both basic pediatric science and clinical research. The Principal Investigator and Program Director will be Dr. Michael M. Frank, Chair of the Department of Pediatrics, who has had a long successful career in training and mentoring. He will be supported by three committees. The Selection Committee, composed of members of our department who are experienced investigators and mentors, will assess and rank potential trainees. Recruitment of trainees from under-represented minorities will be a focus of our program. This recruitment will be supported by Dr. Delbert R. Wigfall, Associate Professor of Pediatrics, Associate Dean, and Director of our Institutional Multicultural Resource Center. The Internal Advisory Committee will regularly assess the trainee's progress, the preceptor's mentoring, and the post-training placement and success of the trainees. Based on that review and the direct review of the Program Director, appropriate interventions for individual trainees will be implemented. The External Advisory Board, made up of internationally recognized successful academic pediatricians from across the United States, will review the accomplishment of the program goals, advise the Program Director as to the overall direction of the program, and help ensure the successful transition of the trainees into academic pediatrics. The program will have four trainees each year. The duration of training will be two to three years. A strong mentored research experience will be provided through interaction with successful clinical and basic pediatric scientists with established track records of mentoring. All trainees will take the course, Responsible Conduct of Research, and a course in grant and manuscript writing. They will develop their communication skills by giving seminars and other presentations. The trainees, depending on their track, will take courses that lead to a Master in Health Sciences degree or to a Master in Genomic Applications to Human Disease degree and will report regularly to the Program Director and the External Advisory Committee. Obtaining the master's degree will be elective, but it is anticipated that most trainees will elect to take the degree. The trainees will be provided career counseling by their mentors, the Internal Advisory Committee, and the Program Director. Our previous success in training fellows who hold academic positions supports the long-term goal of this Institutional National Research Service Award to develop successful academic pediatric scientists who will stay committed to research.

PROPOSAL: 0553518
INSTITUTION: Florida State University
PI: Michael Frank
TITLE: Travel Support for Junior Researchers Attending the Workshop on Frontiers of Extreme Computing

A workshop on "The Frontiers of Extreme Computing: Transitioning Moore's Law to the Next Generation" (www.zettaflops.org) took place October 23- 27 2005 in Santa Cruz, California,. This workshop is an interdisciplinary meeting which aims to call attention to a range of important but not widely-known potential solutions for moving beyond near-term barriers to substantial further improvements in computer performance. The workshop identified important supercomputing applications, matched these against several technologies and programming methods, and determined the suitability of each application at several scale levels. The resulting matrix is a component of a roadmap for further supercomputer development. This award provided travel support for junior researchers.

The results of the workshop will be disseminated widely over the Internet.

DESCRIPTION (provided by applicant): HIV/AIDS continues to cause enormous morbidity and mortality. Developing a vaccine that induces broadly reactive, neutralizing anti-HIV antibody is critically important, but so far no vaccine has been effective. A few such antibodies have been isolated from individual B cells of patients proving that they can be generated. Several of these antibodies have been shown to be polyspecific;they react with multiple antigens in addition to HIV, and they resemble antibodies formed in a part of the spleen termed the marginal zone (MZ). Cells of the MZ are first responders and act to destroy an initial inoculum of virus or bacteria before there is time to make a specific immune response. MZ B cells can also be stimulated to migrate to B cell follicles within the spleen, carrying their antigen. In the follicle, a more specific, high affinity antibody, like most of the antibody formed in AIDS patients, is generated. We focus on the known ability of HIV-1 and all retroviruses to mediate surface binding of proteins of the classical complement pathway, even in the absence of antibody, without being killed. There are three pathways of complement activation. Two of these prove critical. Most viruses and bacteria bind proteins of the alternative complement pathway. These proteins are designed to target and help destroy an initial inoculum of microbes, even before specific antibodies are formed. Most organisms do not bind proteins of the classical pathway. We have made the novel observation that the classical and alternative complement pathways direct antigens to entirely different sets of cellular receptors and can mediate different in vivo consequences. The binding of classical pathway proteins, but surprisingly not alternative pathway proteins, directs antigens to CD21, the C3d receptor, on MZ cells. We suggest that HIV uses this complement activating mechanism to mediate a critical stage in its life cycle. The classical complement proteins act as cofactors in triggering the transfer of MZ B-cells to the germinal center of the follicles where they are positioned for efficient transfer of virus to CD4 T cells. They also initiate a highly specific, but not broadly neutralizing, antibody response. The efficient transfer of MZ cells prevents the essential MZ polyspecific antibody response, required for initial protection. Antibody in antigen/antibody complexes is known to act as an adjuvant in immunization. We hypothesize that by using HIV antigen/antibody complexes prepared with antibodies that only activate the alternative complement pathway as a vaccine, the cycle will be interrupted. An appropriate broadly neutralizing, broadly specific antibody response will be generated by cells of the MZ, thus protecting patients from HIV infection. PUBLIC HEALTH RELEVANCE: The development of an effective, broadly neutralizing anti-HIV vaccine is a national priority. Thus far no vaccine has effectively prevented HIV infection. We propose a new strategy for the generation of an effective HIV vaccine, based on a new understanding of the role of complement in the life cycle of the organism.

How humans regulate their behaviors is a fundamental question. With funding from the National Science Foundation, Dr. Michael Frank of Brown University is investigating interactions between different brain regions involved in how people monitor, learn, and control their actions. This research project focuses on how humans accomplish restrained control over behavior when confronted with difficult decisions. Theoretical models and empirical results suggest that the prefrontal cortex and the basal ganglia interact during these motivated behaviors, and that the neurochemical dopamine plays a central role in both the prefrontal cortex and basal ganglia brain regions. Using electroencephalography (EEG), the investigators are measuring participants' brain waves associated with prefrontal cortex activity, while they perform computerized cognitive tasks that assess learning and decision making in difficult circumstances. The brain wave activity is expected to predict participants' cognitive performance on these tasks. Critically, this brain-behavior relationship is predicted to differ as a function of genetic variants in dopamine function in both the prefrontal cortex and basal ganglia. In another experiment, researchers are directly manipulating dopamine pharmacologically in order to determine how these brain and behavior relationships are causally altered by dopamine levels. In all of their studies, the investigators use detailed mathematical models guided by contemporary theory to isolate specific brain-behavior relationships. It is theorized that both genetic variants and pharmacological manipulations affect the way that the brain monitors, learns, and controls actions. The brain wave measures are allowing the research team to define how neurochemicals modulate the processes of large neural systems.

This research has the goal to substantially advance our understanding of how humans are able to regulate their behaviors as a function of motivation and cognitive control. Scientists widely appreciate that there are large individual differences in these types of motivated behaviors, but only recently have they begun to understand some of the factors governing these differences. By combining multiple research approaches, this project is posed to reveal the ways in which genetic and neurochemical factors alter activity in brain areas that are critically involved in such behaviors. The project also has the potential to identify mechanisms that disrupt brain circuitry and lead to disorders in motivated behavior and cognitive control, including addiction and obsessive compulsive disorder among others.

DESCRIPTION (provided by applicant): The primary purpose of this program has been and will continue to be the training of young physicians with strong academic potential in such a way that they will qualify for full-time medical school faculty positions as allergists and clinical immunologists. Upon completion of his or her training, such a physician should be capable not only of directing research in allergy and immunology but of teaching other physicians the fundamental concepts and clinical expertise necessary for optimum care of patients with allergic and immunologic disorders. The program will place strong emphasis on research training and acquisition of basic immunologic knowledge. These goals will be accomplished through: 1) formal courses in basic immunology and other related disciplines, 2) precepted research training in immunology and molecular biology, and 3) limited clinical exposure to a variety of allergic and immunologic problems so that experience can be gained in the evaluation of patients with these disorders. The training of these fellows in allergy and clinical immunology will take place in the Departments of Pediatrics, Medicine and Immunology. The program will be conducted by twenty-one full-time faculty members who are either allergists and clinical immunologists, rheumatologists, pulmonologists or basic science immunologists;twelve hold M.D. degrees;eleven hold Ph.D. degrees;eight are certified by the American Board of Allergy and Immunology;and three are certified in Clinical and Laboratory Immunology. Nine of these faculty members are members of the Department of Pediatrics;five are members of the Department of Medicine;two are members of the Department of Pathology, one with a joint appointment in Molecular Genetics and Microbiology;and five are primary members of the Department of Immunology and five more hold joint appointments in that Department. The proposed program has a good record of accomplishment over the past 30 years. This application requests support for three trainees each year. The research training will center on research currently ongoing in the various faculty members'laboratories or in the laboratories of other collaborating basic scientists within the Medical Center. Fulfillment of the program's objective would directly or indirectly serve to meet two urgent medical needs: 1) the need for more full-time researchers and teachers of allergy and clinical immunology in medical schools throughout the country and 2) the need for more physicians trained in the specific care of patients with allergic and immunologic disorders. PUBLIC HEALTH RELEVANCE: To develop innovative pediatric physician-scientists trained in the latest methods of laboratory and clinical research and fully prepared to pursue independent academic careers investigating critical issues in allergy and clinical immunology. These trainees will become key mentors to future pediatric physician-scientists.

This research project investigates the nature of interactions between different brain regions involved in how people learn and control their actions. Theoretical models and empirical data suggest that the prefrontal cortex (PFC) and basal ganglia (BG) interact in these types of motivated behavior, and that the neurochemical dopamine plays a central role in both of these brain regions. However, it has been difficult to isolate the separable contributions of these different brain systems to learning. Dr. Frank and colleagues will investigate how PFC augments human reinforcement learning by leveraging its well-studied roles in working memory, cognitive control, abstraction, and rule representation. This work has potential to substantially advance our understanding of how humans are able to regulate their behaviors as a function of motivation and cognitive control. Learning impairments are prevalent in many psychiatric disorders. While in some cases, such as Parkinson's disease, the mechanisms involved are relatively well understood, in others, such as schizophrenia, the underlying deficits are poorly characterized. It is crucial to properly isolate different components contributing to learning, so as to appropriately relate them to separable mechanisms giving rise to those deficits. If learning is considered as a unitary system, learning deficits that arise due to impairments in one process and brain system may be mistakenly attributed to the other system and lead to erroneous conclusions. Following the same approach will shed light on the actual cause of learning impairments. As such, this research has the potential to identify mechanisms that explain how disruption of such brain circuitry leads to disorders in motivated behavior, cognitive control, and impulsivity. Similarly, developmental learning disabilities may involve a deficit in abstraction and generalization. The aim is to better understand the underlying mechanisms and computations needed for such functions. Drs. Frank and Collins will also provide mentoring on computational and data analytic methods for under-represented women in the STEM disciplines.

Computerized experimental tasks will manipulate factors thought to depend on PFC function, including working memory load and the degree to which the discovery of coherent rules can be used to speed learning. Dr. Frank and colleagues use mathematical modeling to separately estimate the contributions of PFC function from that of basic BG processes. Using electroencephalography (EEG), the investigators will measure human participants' brain waves associated with PFC activity while they perform these tasks. Brain wave activity is expected to predict cognitive performance on these tasks. Critically, this brain-behavior relationship is expected to differ as a function of genetic variants that reflect differences in dopamine function in PFC and BG. Another study will directly manipulate dopamine (pharmacologically) in order to determine how these brain and behavior relationships are causally altered by dopamine levels. In all of these studies the investigators use detailed mathematical models to isolate specific brain-behavior relationships guided by contemporary theory. It is expected that genetic variants and pharmacological manipulations will affect the way that the brain learns from decision outcomes and controls actions.

Mental Abacus is a popular mathematics technique practices primarily in Asian countries in elementary school contexts. Mental abacus students begin by learning to make rapid arithmetic computations on a physical abacus and then learn to imagine moving the beads without the physical device. Young children can then rapidly add, subtract, multiply and divide large numbers. This project will compare mental abacus teaching to two other teaching methods in order to understand how it helps first and second grade students learn to compute and learn conceptual understanding of place value. The ECR program emphasizes fundamental STEM education research that generates foundational knowledge in the field. Investments are made in critical areas that are essential, broad and enduring: STEM learning and STEM learning environments, broadening participation in STEM, and STEM workforce development.
Prior work indicates the mental abacus computations are connected to visuo-spatial working memory. The project is a randomized experiment to compare the effectiveness of Mental Abacus, Singapore Math Curriculum and business-as-usual curriculum in grades 1 and 2 in multiple elementary schools. Math outcomes will be measured with standardized test scores and four assessments (an in-house arithmetic fluency measure, the WIAT, the Woodcock-Johnson III, and a measure of conceptual understanding of place-value). A battery of cognitive measures and a measure of intervention fidelity will also be included. The project should result in understanding the effectiveness of Mental Abacus as a method for teaching and provide a foundation for larger scale work in the area.

People often mean more than they say. To take an example, imagine Adam says "I could use a cup of coffee" and Bob responds by saying "There's a place called Joe's around the corner." We understand this as a coherent exchange even though Adam's utterance wasn't phrased overtly as a question and Bob didn't explicitly say that Joe's sells coffee. Extracting this rich additional meaning requires us to consider sentences in light of both the context they are used in and the cooperative motivations of Adam and Bob in using language (what are called "pragmatic inferences"). This project is devoted to constructing formal models of these pragmatic inferences. Modeling pragmatic inference is a major scientific challenge in the study of language and the human mind and a key to the future development of autonomous intelligent systems that can communicate with humans using natural language. Machines that can do robust language understanding in context will pave the way for societally beneficial technological applications such as adaptive intelligent tutoring and assistive technologies.

The technical core of the project involves developing and extending models of pragmatic reasoning, drawing on ideas and insights from decision theory, probabilistic models of cognition, bounded rationality, and linguistics. In particular, the work extends the recently developed family of "rational speech act" models, which provides a set of formal tools that can be used to address basic challenges in psycholinguistics concerning how major principles of pragmatic inference fall out of simple assumptions about cooperativity and shared context among conversation participants. This enterprise has the potential to fill a major open theoretical gap in our scientific understanding of human language and social cognition. Project work includes developing computational Bayesian models of semantic composition and pragmatic inference and testing those models using controlled psycholinguistic experiments. The work will also yield new models and publicly available datasets and will contribute to interdisciplinary connections by creating and reinforcing links between linguistics, psychology, and computer science.

Learning language is one of the most impressive and intriguing human accomplishments. Early language skills set the stage for later cognitive development and academic achievement. The goal of this project is to develop a powerful tool for researchers interested in typical and atypical language development to better understand young children's earliest language. This tool, called Wordbank, is a structured database of parent reports about children's vocabulary that combines tens of thousands of reports completed by parents whose children have participated in child development research. Wordbank will include data from research laboratories in dozens of countries, collected over many years and including many of the world's languages. This database will be useful for understanding generalizable trends across languages and cultures as well as exploring reasons that individual children might differ in their language development. Such a rich source of information will allow for novel insights that could not be discovered in smaller samples.

Wordbank will make use of the MacArthur-Bates Communicative Development Inventories (CDIs), a widely-used family of parent-report instruments that are designed for easy and inexpensive data-gathering about children's early language acquisition. Wordbank will archive CDI data across languages and labs in an item-by-child format relational database. Built on open-source analytic tools, the site will host in-depth exploratory visualizations and facilitate the productive reuse of data. In addition to an interactive interface for exploration, the website will also allow researchers to connect directly to the underlying database. The result will be a resource that enables new discoveries about early language across a variety of disciplines.

This site is supported by the Department of Defense in partnership with the NSF's Research Experiences for Undergraduates (REU) Sites program. The REU program has both scientific and societal benefits integrating research and education. Recent developments in cognitive science have led to breakthrough new scientific results and are providing the basis for exciting new applications in areas like social computing and assistive technologies. These developments present a challenge for education, however. Even at top research universities, students are hard-pressed to receive the appropriate training; the situation is even more difficult at institutions that do not provide extensive research training. This REU addresses this challenge. Based at Stanford's Center for the Study of Language and Information (CSLI), a top institution for interdisciplinary cognitive science, the program provides talented undergraduates from diverse backgrounds with both an opportunity to do mentored research in a top laboratory and a supportive program framework that includes technical training, professional development, and academic discussion.

The scientific and technological innovations motivating this REU derive from a convergence within the core disciplines of cognitive science -- psychology, linguistics, and computer science -- around themes of uncertainty, approximation, and learning. As psychology and linguistics are becoming more computational, computation is returning to its cognitive roots. Artificial intelligence techniques developed in psychology are undergoing a resurgence in machine learning, and natural language processing models of syntactic structure are becoming the standard cognitive modeling frameworks in psycholinguistics. The prerequisites for research in this new intellectual environment include an understanding of how the mind works, familiarity with the nature of human language and communication, proficiency in statistical analysis, and advanced programming skills. Yet a classic psychology or linguistics degree provides almost no programming or technical experience, and a standard computer science education doesn't include any content on how the mind works. This REU fills such gaps in the training of undergraduates and helps to foster a new, more diverse generation of researchers entering cognitive science.

Our training program for Interactionist Cognitive Neuroscience (ICoN) seeks to provide student-focused, interdisciplinary training in computational cognitive neuroscience that integrates data from multiple scales and levels of analysis. Transformative gains in understanding the human brain and mental health require integration across multiple levels of analysis. Recent historic advances in genetics and cellular biology are paving the way for understanding fundamentals of neural function. At the other end of the spectrum, methods for imaging and stimulating human brains non-invasively have led to revolutionary advances in discovering the macro-scale organization supporting perception, motivation, and cognition. Now, a major effort at the `systems' level between these two scales is beginning to uncover the activity, connectivity, and computations of neural circuits. The advent of this systems-level progress holds the promise of linking core circuit computations to emergent human behavior and leading to detailed, transdiagnostic models of mental illness. However, as we recently argued (Badre, Frank and Moore, 2015 Neuron), fulfilling this promise requires making direct links between circuit-level computation and the emergent function of the human system. We believe that integrating systems- and human neuroscience in this way demands a systematic approach built on two key strategies. First, formal computational models must be used to provide principled links between levels of analysis; and, second, complementary methods must be applied, and in the ideal case parallel human and non-human studies conducted in coordination. Achieving these aims requires a new generation of scientists that can take full advantage of multiple techniques and data sources, and who are deeply versed in computational theory. Traditional neuroscience training relies on an apprenticeship model that limits students to a single lab and level of inquiry. Thus, a specialized training program is required to specifically equip neuroscientists for this `Interactionist' approach. ICoN will provide this training emphasizing the two tenets: I. Computation is key to translating between levels. Students must be rigorously quantitatively trained in formal theory. A close corollary is that they must be fluent in the advanced analysis methods necessary for cross-level integration (e.g., machine learning). II. Next-generation scholars must have expertise at multiple levels. Students must be trained to use and integrate multiple methods and data sources. Further, they must have the skills (and courage) to pursue ideas to their next most logical step, to be question driven and not technique limited. Students will be trained to conduct integrative research projects across domains such as human cognitive neuroscience, systems neuroscience, and computational neuroscience.

The goal of understanding psychiatric disorders and advancing psychiatric treatments requires basic knowledge of not only what environmental, genetic and epigenetic factors underlie function and dysfunction, but also how these factors alter the circuit-level computations that are the proximal neural events to behavior. The advent of research in this area holds the promise of linking core computations of neural circuits to complex human behavior, with the ultimate goal of developing comprehensive, multilevel transdiagnostic models of neuropsychiatric disorders. Consequently, the emerging field of computational psychiatry is central to the NIMH mission. Despite its importance, there are very few opportunities to pursue training in this area. Consequently, the proposed training program seeks to take recent PhDs, with strong backgrounds in fields such as neuroscience, engineering, applied math, and computer science, and provide them with the tools to make important contributions to the nascent field of computational psychiatry. The proposed Training Program in Computational Psychiatry (TPCP) will take place at Brown University where there is a critical mass of basic researchers on the main campus and clinical researchers in the Department of Psychiatry and Human Behavior to conduct such a training program. We propose enrolling six fellows (3 per year) in the TPCP with the goal of training, more efficiently and effectively, nonclinical research fellows capable of collaborating with clinical researchers to advance knowledge of psychiatric disorders and treatments. The program embraces an apprenticeship model in which fellows work with a primary research trainer in a computational field and a secondary research mentor in clinical psychiatry. In this apprenticeship model, the trainer works closely with the fellow and a secondary clinical psychiatry mentor, who is conducting research in areas such as neuroimaging, neurostimulation, and digital phenotyping. These research areas are especially conducive to addressing important issues in computational psychiatry, whether they be model/theory-driven or data-driven. The proposed didactic program will include both core seminars and an individualized curriculum including fellow-selected courses in neuroscience, computer science, engineering, applied mathematics, or psychiatric disorders. All fellows attend core seminars on grant writing, responsible conduct of research, and rigor and reproducibility. The short-term final product is an NIH grant application on a computational psychiatry topic. The long-term goal is to produce a new cohort of academics who can conduct research in computational psychiatry and train the next generation of graduate students in this emerging field of inquiry.