Daniel Savage - US grants

NMARC's Administrative Core is responsible for providing scientific and administrative leadership for the entire center program along with the administrative support and budgetary oversight of all NMARC-related activities. Operational supervision of the NMARC is provided by a three-tiered system of management: 1) The Administrative Core, 2) the NMARC Steering Committee whose collective knowledge and experience represents the breadth of NMARC activities and, 3) the NMARC Program Advisory Committee (PAC) composed of seven internationally-renowned FASD research investigators. The specific aims of the Core are to: 1) Provide administrative leadership and support for the NMARC. All NMARC investigators receive routine administrative support. The Core also arranges all NMARC-related meetings, manages logistical arrangements for NMARC seminar visitors, the Annual Symposium and the Annual Meeting with the PAC. The Steering Committee meets monthly to review progress on the research components and resource allocation issues. The Steering Committee also meets with the PAC during the Annual NMARC meeting to discuss each research component's progress, the operation and coordination of the Administrative, Scientific and Pilot Project cores and the center's overall progress towards the achievement of the specific aims of the center as a whole. 2) Provide scientific leadership and direction to NMARC's investigators, working to help them achieve the aims of their individual research projects while advancing the specific aims of the center as a whole. The Core will facilitate research collaborative interaction and communication through the monthly Scientific Core meetings with component investigators, working to increase the integration of preclinical and clinical research projects and the interactions with NMARC's core facilities. The Core will also work to build NMARC's research capacity through oversight of a pilot project program, continued efforts to recruit new faculty investigators to NMARC, building research collaborations with other institutions and encouraging the training of future FASD investigators. 3) Manage all issues related to resource allocation within the NMARC and strive to maximize the synergistic utilization of research resources within the center. The Core will coordinate and facilitate NMARC investigator access to other resources within the university. 4) Enhance our knowledge dissemination capabilities through our NMARC Seminar Series, an Annual NMARC Symposium, a NMARC Webpage and expanding our community outreach activities. Assessment of NMARC's progress towards the achievement of these aims and the strategic objectives will be the responsibility of the Steering Committee working in conjunction with the Program Advisory Committee.

DESCRIPTION (provided by applicant): NMARC is a NIAAA-designated Developmental Alcohol Research P20 Center at the UNM Health Sciences Center. The center is comprised of teams of preclinical and clinical scientists with a history of collaborative research interactions whose expertise and contributions have synergized the center's research environment and is facilitating progress towards the achievement of NMARC's three strategic objectives. These objectives are to: 1) Advance our understanding of the teratogenic consequences of fetal alcohol exposure that cause functional brain damage leading to adverse neurobehavioral outcomes. 2) Develop more effective approaches for diagnosing individuals with FASD through the establishment of more sensitive and reliable alcohol biomarkers of alcohol exposure coupled with the use of novel neurobehavioral and functional neuroimaging assessments that can detect functional brain damage earlier in life. 3) Develop more effective neurobehavioral, educational and pharmacotherapeutic interventions tor fetal alcohol-related behavioral deficits. NMARC's prevailing philosophy is that a research center organized to maximize the coordination, communication and synergistic integration across multiple lines of preclinical and clinical investigation provides the best long-term prospect of achieving significant progress towards the dual clinical goals of better diagnosis and more effective interventions for FASD. This P50 grant application contains five research components, each consisting of teams of investigators whose project addresses one or more of NMARC's three strategic objectives. Three core components support the center's research program: 1) A Pilot Project Core with one clinical and two preclinical projects led by investigators new to the FASD research field. 2) A Science Core that supports all NMARC investigators and serves as a forum for catalyzing collaboration and peer group mentoring. 3) An Administrative Core that will provide scientific and administrative leadership for the entire NMARC program along with administrative support and budgetary oversight of the center programs. The Administrative Core will also be responsible for ensuring progress toward achieving the center's goals of building research capacity through the recruitment of other UNM faculty and new faculty hires, and enhancing our knowledge dissemination capabilities. Assessment of NMARC's progress and achievements will be the responsibility of the Steering Committee working in conjunction with an external Program Advisory Committee of seven internationally-renowned FASD scientists, who will advise and assess NMARC's research activities and progress towards the achievement of the center's goals and strategic objectives.

PROJECT SUMMARY ABSTRACT Learning disabilities are the most common behavioral deficit observed in children with Fetal Alcohol Spectrum Disorder (FASD). Currently, there are no established rationally-based clinically-effective pharmacotherapeutic interventions for these and related behavioral deficits. However, using a well-established rat model of FASD, we have observed that the histamine H3 receptor inverse agonist ABT-239 ameliorates prenatal alcohol exposure (PAE)-induced deficits in dentate gyrus long-term potentiation (LTP) and retention of memory. We have also observed increased H3 receptor-effector coupling and a heightened H3 receptor-mediated inhibition of glutamate release in the dentate gyrus of PAE rats. Our results suggest that PAE increases H3 receptor-mediated inhibition of glutamate release and that ABT-239 reduces this heightened inhibitory influence. These observations provide preclinical rationale for examining the efficacy of H3 receptor inverse agonists on treating learning and memory deficits in children with FASD. The working hypothesis for the preclinical UH2 phase of this proposal is that SAR152954, another histamine H3 receptor inverse agonist, will ameliorate PAE-induced behavioral and synaptic plasticity deficits by reversing PAE-induced decreases in activity-dependent potentiation of glutamate release. We will first examine the effects of four different doses of SAR152954 on PAE-induced deficits in one- trial contextual fear conditioning (Aim 1A) and the retention of spatial memory using the Morris Water Maze (Aim 1B), two behaviors quite sensitive to PAE-induced functional damage of the dentate gyrus. The milestone objective of Aim 1 will be to identify the optimal test dose (OTD) of SAR152954 that reverses PAE-induced memory deficits. Subsequently, we will examine whether the OTD dose of SAR152954 reverses PAE-induced deficits in dentate gyrus LTP (Aim 2A) and putative deficits in activity-dependent potentiation of glutamate levels in dentate gyrus (Aim 2B). The milestone objective of Aim 2 will be to demonstrate the amelioration of these neurophysiological deficits as the mechanistic cornerstone of a preclinical rationale for advancing H3 receptor inverse agonists to clinical trial. Assuming we achieve the preclinical milestones, we will submit a one-year request for funding to develop a clinical trial plan. A tentative draft of plans has been developed by our clinical investigator team. First, a Phase Ib trial is proposed using three drug doses in adolescents with FASD. In addition to acquiring pharmacokinetic and safety profile data, the primary Phase Ib milestone objective will be to identify the highest safe dose of the agent producing significant improvements in combined behavioral and neurophysiologic responses, as measured using hdEEG/magnetoencephalography. Subsequently, in a Phase IIa clinical trial, we would assess the therapeutic efficacy of the optimal drug dose using a double-blind crossover design that employs the same pharmacodynamic assessments used in the Phase Ib trial. Assuming these UH3 milestones are achieved, we anticipate a subsequent, more extensive trial to assess drug efficacy in a multisite clinical trial.

PROJECT SUMMARY ? ADMINISTRATIVE CORE NMARC's Administrative Core is responsible for providing scientific and administrative leadership for the entire center program along with the administrative support and budgetary oversight of all NMARC-related activities. Operational supervision of the NMARC is provided by a three-tiered system of management: 1) The Admin Core Executive Committee. 2) The NMARC Steering Committee, composed of four directors and senior researchers from UNM and the MIND Research Network. 3) The NMARC Program Advisory Committee (PAC) composed of seven internationally renowned FASD research investigators. The Admin Core has four specific aims: Aim 1) Provide administrative leadership and support for the NMARC. All NMARC investigators receive routine administrative support. The Admin Core also arranges all NMARC-related meetings, manages logistical arrangements for NMARC seminar visitors, the Annual FASD Day Symposium, and the Annual NMARC Meeting with the PAC. The Steering Committee meets twice a year to review progress on the research components and discuss any resource allocation issues. The Steering Committee also meets with the PAC during the Annual NMARC meeting to discuss each research component's progress, the operation and coordination of the Administrative and Pilot Project cores, and the center's overall progress towards the achievement of the specific aims of the center as a whole. Aim 2) Provide scientific leadership and direction to NMARC's investigators, working to help them achieve the specific aims of their individual projects while advancing the specific aims of the center as a whole. The Admin Core will facilitate collaborative research interaction and communication through the monthly NMARC Investigator Group meetings with all NMARC-affiliated investigators, working to increase the integration of preclinical and clinical research projects. The Admin Core will also work to build NMARC's research capacity through oversight of the pilot project program, continued efforts to recruit new faculty investigators to NMARC, building research collaborations with other institutions and encouraging the training of future FASD investigators. Aim 3) Manage all issues related to resource allocation within the NMARC and strive to maximize the synergistic utilization of research resources within the center. The Admin Core will coordinate and facilitate NMARC investigator access to other resources within the university. Aim 4) Enhance our knowledge dissemination capabilities through our NMARC Seminar Series, the Annual FASD Day Symposium, a NMARC Webpage, and expanding our community outreach activities. Assessment of NMARC's progress towards the achievement of these aims and the strategic objectives is the responsibility of the Steering Committee working in conjunction with the PAC.

PROJECT SUMMARY - OVERALL NMARC is a NIAAA-designated Alcohol Research P50 Center at the UNM Health Sciences Center. The center is comprised of teams of preclinical and clinical scientists with a history of collaborative research interactions whose expertise and contributions have synergized the center?s research environment and is facilitating progress towards the achievement of NMARC?s three strategic objectives. These strategic objectives are to: 1) Advance our understanding of how prenatal alcohol exposure affects basic neurobiological mechanisms resulting in functional brain damage which can lead to life-long adverse neurobehavioral consequences. 2) Develop more effective approaches for the diagnosis of individuals with FASD through the establishment of more sensitive and clinically reliable biochemical, physiological and neurobehavioral biomarkers of alcohol exposure that are detectible early in life, are prognostic of functional brain damage, and could predict long-lasting neurobehavioral consequences in patients with FASD. 3) Develop interventions that are more effective for prenatal alcohol- related behavioral deficits. Better interventions may ultimately require combinations of neurobehavioral, educational and/or pharmacotherapeutic approaches to ameliorate the often subtle, but long-lasting impact of prenatal alcohol-induced behavioral problems. NMARC?s prevailing philosophy is that a research center organized to maximize the coordination, communication and synergistic integration across multiple lines of preclinical and clinical investigation in these three strategic objective areas provides the best long-term prospect of achieving significant progress towards the dual clinical goals of better diagnosis and more effective interventions for patients with FASD. NMARC?s specific aims as an integrated whole during the P50 Phase II will continue to be to: 1) Accelerate progress on each on NMARC?s three strategic objectives. 2) Catalyze the expansion of NMARC?s research capacity and capabilities. 3) Enhance our capability to disseminate knowledge about FASD through seminars, symposia and community outreach activities. 4) Increase the number of undergraduate and graduate students, fellows and residents training in the FASD research field. This P50 competing renewal contains four research components, each consisting of teams of investigators whose projects address one or more of NMARC?s three strategic objectives. Two core components support the center?s research program: 1) A Pilot Project Core with two two-year projects involving faculty investigators new to the FASD research field. 2) An Administrative Core that provides scientific and administrative leadership for the entire NMARC program, along with administrative support and budgetary oversight of all NMARC-related activities. The Administrative Core is also responsible for ensuring progress toward achieving the specific aims of the center as a whole. Assessment of NMARC?s progress towards the achievement of these aims and the strategic objectives is the responsibility of the Executive and Steering Committees working in conjunction with our external Program Advisory Committee comprised of seven internationally renowned FASD scientists.

PROJECT SUMMARY Learning disabilities are the most common behavioral deficit observed in patients with Fetal Alcohol Spectrum Disorder (FASD). Currently, there are no established clinically effective pharmacotherapeutic interventions for these behavioral problems. Using a well-established rat model of FASD, we have reported that the histamine H3 receptor inverse agonist / antagonist ABT-239 ameliorates prenatal alcohol exposure (PAE)-induced deficits in synaptic plasticity and learning. We have also observed increased H3 receptor-effector coupling and a heightened H3 receptor-mediated inhibition of the probability of glutamate release in dentate gyrus of PAE rats. Collectively, these results suggest that PAE increases H3 receptor-mediated inhibition of glutamate release and that ABT-239 reduces this heightened inhibitory influence. One parsimonious explanation for why PAE rats are more sensitive to H3 receptor agents is a PAE-induced increase in the expression of the rH3A isoform of histamine H3 receptors relative to the rH3C isoform. This putative shift would confer greater sensitivity to the inhibitory effects of histamine H3 receptor agonists in PAE rats. The principal objectives of this NMARC research component application are to: 1) Examine whether PAE increases the expression of rH3A relative to rH3C in entorhinal cortical neurons projecting to the dentate gyrus. 2) More thoroughly establish the consequences of a PAE-induced elevation in H3 receptor-effector coupling and the effects of second H3 receptor inverse agonist / antagonist namely, SAR152954, on H3 receptor-mediated inhibition of glutamatergic neurotransmission in dentate gyrus. In Specific Aim 1A, we will employ in situ hybridization and qRT-PCR approaches to first confirm whether PAE increases the rH3A/rH3C mRNA expression ratio. In Aim 1B, we will use a [35S]-GTP?S binding assay in histological sections to conduct a more detailed examination of the effects of PAE on H3 receptor- effector coupling and assess the differential sensitivity of PAE rats to SAR152954 relative to controls. In Specific Aim 2A, we will conduct in vitro slice physiology studies to examine: 1) The impact of PAE on the effects of the H3 receptor agonist methimepip on fEPSP responses and pair-pulse plasticity in dentate gyrus, under baseline and after theta burst stimulation conditions. 2) The effects of SAR152954 alone and in the presence of methimepip on paired-pulse ratio and long-term potentiation. In Aim 2B, we will examine the impact of PAE on fEPSP and PPR before and after high frequency stimulations in awake freely moving rats. We predict that SAR152954 will ameliorate the heightened H3 receptor mediated inhibition of synaptic plasticity in PAE rats at concentrations/doses that do not impair synaptic transmission in control rats. These studies address two of the three strategic objectives of NMARC, namely advancing our understanding of the neurobiological consequences of PAE, as well as working towards establishing the mechanistic basis for novel interventions to treat of PAE- induced deficits in synaptic plasticity and memory. These studies could provide additional preclinical rational for considering drugs such as SAR152954 for clinical trials in patients with FASD. 1