Steven E. Hyman, M.D. - US grants

Cytokines, which have long been known to regulate immune function and hematopoiesis, have recently been shown to exert powerful effects on neural gene expression, proliferation, and survival. Indeed the boundaries between peptides classified as cytokines and as neurotrophic factors has been increasingly blurred. For example, cytokines such as interleukin-1=DF (IL-1=DF) which act in the periphery to modulate the immune response, act within the hypothalamus to regulate overall organismic adaptations to infection, inflammation, and stress. Other cytokines, such as leukemia inhibitory factor (LIF), appear to be involved in the adaptation of the nervous system to injury, and are closely related to factors involved in neuronal survival and phenotype determination. Little is known to date about the molecular mechanisms by which cytokines regulate transcription of neural genes, and even less is known about the interactions among cytokine and neurotransmitter signaling pathways. The proenkephalin gene, which encodes the opioid peptides met- and leu-enkephalin, has served as an important model of transcriptional regulation in the nervous system; therefore much is known about proenkephalin gene structure and regulation. Because proenkephalin gene expression is regulated not only by neurotransmitters and drugs of abuse, but also by multiple cytokines, including both IL-1=DF and LIF, we propose to use the proenkephalin gene as = a model to elucidate the molecular actions of these representative and physiologically significant cytokines in the nervous system. We propose to use primary cultures of glia and hypothalamic neurons and the hypothalamus in intact animals, including transgenic mice, to study cytokine signalling pathways, their interactions with neurotransmitter signaling pathways, and their modulation by opioids. The resulting information should contribute, in addition, to our understanding of interactions between the nervous system and the immune system, and of the potential impact of drugs of abuse on these interactions, as may occur in active drug abusers with AIDS.

The primary objective of this project is development of an Institutional Review Board (IRB) process management system -- HIRBERT: Harvard IRB Electronic Reporting Tool -- with a common technology platform that will serve the University's three independent IRB's by facilitating and automating the protocol approval process. We envision HIRBERT as a highly flexible multi-user system that will replace three stand alone legacy systems. Development of a single system will allow for standardization of IRB data across the University without sacrificing the distinct needs of each office. It will also allow for a coordination of IRB activity not previously available. At the conclusion of the project HIRBERT will support and enable an automated approval process; allow for direct entry of application and renewal data by IRB administrative staff; support and enable agenda, minutes, letters and notification templates; strengthen and streamline the continuing review process; and link compliance and IRB processes. It will provide the IRB offices with the ability to meet University, study, investigator and sponsor reporting needs and current and anticipated federal reporting requirements. HIRBERT will provide the University with an infrastructure upon which to build a Web-based electronic protocol submission process for investigators. It will greatly reduce the burdensome administrative demands on the IRB staff thereby enabling them to devote more attention to substantive protection issues.

The objective of this project is development and delivery of a module-based human subject protection training program in five major world languages (English, Arabic, Chinese, French, and Spanish) linked to HIRBERT, Harvard's IRB Electronic Reporting Tool. The new program brings together in one on-line system all of the training offerings of the University's three IRB's for IRB members, faculty, and research staff. Modules will include units devoted to IRB member training; a primer for student researchers; and a range of modules for faculty and researchers encompassing common and IRB specific topics. Special attention will be directed at development of modules that address behavioral and social science issues, an underserved area in most human subject protection programs. The program will also include more clinically oriented modules appropriate for research at Harvard's affiliated hospitals. Translations of the program into Arabic, Chinese, French, and Spanish will be made available in hard copy or electronically to current international collaborators, as well as non-collaborators in Asia, Africa, and Latin America, at no cost. Access to the program will also be provided, at no cost, to colleges and universities not eligible for NIH funding.