CORE FACILITIES

1. The Center for Translational Neuroscience after 4 years E Garcia-Rill, PhD Center for Translational Neuroscience, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR Major Discoveries, New Treatments, Patents MENTORED SCIENTISTS RESULTS ABSTRACT • Investigators- • John Dornhoffer, MD, mentored by the Year 1 Recruit M. Mennemeier, PhD, 2) Alice Fann, MD, mentored by E. Garcia-Rill, PhD, in Year 1, then by the Year 2 Recruit E. Al-Chaer, PhD, 3) R. Whit Hall, MD, mentored by K.J.S. Anand, MD, in Year 1, then by E. Garcia-Rill, PhD, 4, 5) Thomas Kiser, MD, and Nancy Reese, PT, PhD (UCA), mentored by Visiting Mentor, S. Mori, MD, PhD, and Robert Skinner, PhD, 6) Melanie MacNicol, PhD, mentored by Gwen Childs, PhD, Chair Neurobiology & Dev. Sci., 7) Jeffery R. Kaiser, MD, became Replacement Investigator mentored by Year 3 Recruit, • Hayar, PhD, 8) Catherine Cole, RN, mentored by Year 1 Recruit M. Mennemeier, PhD, 9) Michael Mancino, MD, co-mentored by Drs. Allison Oliveto, PhD, and Edgar Garcia-Rill, PhD, 10) Charlotte Yates, PT, PhD (UCA), mentored by Edgar Garcia-Rill, PhD, William Fantegrossi, PhD, mentored by Michael Borrelli, PhD, will become a Replacement Investigator in Year 5. Pilot Study Awardees- • Yi-Hong Zhou, PhD, received the Year 1 Pilot Study award, • Mary Aitken, MD, Year 2 Pilot Study award, mentored by M. Mennemeier, PhD, • Amanda Charlesworth, PhD, Year 3 Pilot Study award, mentored by E. Garcia-Rill, PhD, • William Fantegrossi, PhD, Year 4 Pilot Study award, mentored by M. Borrelli, PhD. Senior Recruits (Associate Professors)- Year 1- Mark Mennemeier, PhD, recruited from University of Alabama Birmingham, • Year 2- Elie Al-Chaer, PhD, JD, recruited from University of Texas Medical Branch in Galveston, • Year 3- Abdallah Hayar, PhD, recruited from the University of Tennessee Memphis, Junior Recruits (Assistant Professors)- Year 4- Amanda Charlesworth, PhD, Year 5- William Fantegrossi, PhD, Year 5 Recruit. COBRE-INBRE mentoring interactions- • N. Reese, PT, PhD, now Chair of the Department of Physical Therapy at UCA, • R. Buchanan, PhD (UCA)- Chair of the Department of Biology at ASU, • K. Garrison, PT (UCA)- Assistant Professor of Physical Therapy at UCA, • W. Gonzalez, PhD (ATU)- Associate Professor of science education at ATU. Training and Advanced Degrees (not originally proposed)- We advised 3 clinician scientists in the pursuit of higher degrees in neurobiology, • Alice Fann, MD, MS awarded 2005, PhD awarded 2006, • Charlotte Yates, PT, PhD awarded 2007, • David S. Heister, MD/PhD student, PhD awarded 2008. • Other Trainees: 4 Postdoctoral Fellows- Kazuto Ishida, PT, PhD, Asahikawa University, • 2006-2007; Nicolai Karpuk, PhD, Moscow University; Jing Wang, MD, PhD, Fujian Medical • University (MD) & Sun Ya-sen University of Medical Science (PhD); Chunping Gu, MD, PhD, • Harbin Medical University, China. In addition, the CTN trained 4 traditional graduate students, • Patricia Bray, MS awarded 2005; Cameron Good, PhD awarded 2006, now a Postdoctoral • Fellow at NIDA; Tiffany Wallace-Huitt, PhD awarded 2007, now a NRSA-funded Postdoctoral • Fellow at Wake Forest University; and Meijun Ye, currently pursuing a PhD degree. • High School, Undergraduate, Graduate and Medical Students- • DeAnna Mitchell, Undergraduate Research, 2004-2005 (Univ. Wisconsin); • Christina Barnes, Undergraduate Research, 2004-2005 (Stanford Univ.); • Hannah Manire, Undergraduate Research, 2004-2005 (speech therapist); • Richa Thappa, Undergraduate Research (NIH minority suppl.) 2005-2007 (med. student UAMS); • Pryinka Thappa, High School Research (NIH minority suppl.) 2005-2007 (Notre Dame); • Jake Lee, High School summer research, 2005-2006 (UA Fayetteville); • Paige Beck, Undergraduate Research, 2006-2007 (UA Fayetteville); • Matthew Dinehart, High School summer research, 2006 (Rhodes Scholar at Oxford University); • Shelby Bennett, Summer Research Fellowship 2007 (med. student UAMS); • Rami Al-Mefty, Honors Research Fellowship 2007-2008 (minority med. student at UAMS); • Beth Sybert, High School summer research 2007 (now a senior in High School); • Dominick Gruenwald, High School summer research 2007-2008 (High School); • Angela Odle, Undergraduate Research 2007-2008 (Mississippi State Univ.); • Brian Yuen, High School summer research 2007-2008 (High School). Objective: Our aims were to establish 1) a Career Development Program with mentoring/funding for 5 projects and 6 promising investigators without a history of support, 2) a multi-disciplinary Center, a Pilot Study Program, and recruitment of two senior and three junior investigators to build the critical mass of researchers, and 3) two Core Facilities, Administrative and Experimental, to support research. All aims were met and exceeded. Methods: We developed a Career Development Program and Center so that promising clinician and basic scientists could be mentored to secure funding. Results: We have mentored and supported 10 promising investigators without a history of support. In addition to funding 5 projects and 6 investigators with designated Mentors, we provided access to Core Facilities to 4 other investigators, and assigned them Mentors to help guide their efforts. We awarded 5 instead of 4 pilot study grants and assigned Mentors to each recipient to improve output. We recruited 3 senior and 2 junior faculty and established 6 (instead of 2) new Core Facilities. We discovered two new cures, two novel treatments and one new mechanism, all with clinical implications. We generated >$12 million in new awards, published >100 articles and >100 abstracts. Discussion and Conclusions: The oversight of a dedicated external advisory committee and considerable institutional support were critical to our success, along with selfless mentoring by dedicated senior scientists. 1) We found (Project I- Dornhoffer, Mennemeier) that TMS could alleviate tinnitus for weeks at a time, but, more importantly, have now developed a treatment that produces virtually permanent symptom relief after 1-3 treatments. A case report is in press but several other patients have already been found to respond. 2) We found (Project III- Hall, Anand, Wallace-Huitt) that ex-preterm adolescents show a spectrum of arousal, attentional and frontal lobe flow disorders that segregate into three distinct groups who require treatment with different drugs. The ability to diagnose these sub-populations will improve therapeutic outcomes. An intervention designed to reduce these deficits will be incorporated into future studies in order to apply the finding to the clinic. We found (Project IV- Kaiser, Reese) that passive exercise could eliminate hyper-reflexia in spinal cord transected rats, and developed a device for testing in humans, the Motorized Bicycle Exercise Trainer (MBET). A patent was secured and licensed to Ozark Systems Manufacturing, Siloam Springs, AR, which is manufacturing and selling the MBET. We found (Project IV- Reese, Yates) that treatment with a stimulant that increases electrical coupling led to elimination of hyper-reflexia in spinal transected rats. A patent for the novel use of this agent was filed. A number of grant applications have resulted from this finding that are under review. 5) We found (Mennemeier, Garcia-Rill) that spatial neglect due to large strokes of the right hemisphere, which typically do not resolve as do left-sided damage, can be totally alleviated by modafinil, a wake-promoting agent, within days. Spatial neglect due to right hemisphere stroke has been assumed to be untreatable, but every patient to date has responded positively. 6) We found (Charlesworth, Heister, Hayar, Garcia-Rill, Ye) that cells in the reticular activating system controlling sleep and waking are electrically coupled, leading to novel treatments for several disorders. Since some anesthetics block gap junctions and a new stimulant increases electrical coupling, the role of coupling becomes a new mechanism for sleep-wake control. This discovery was featured in the Fall 2007 issue of NCRR Reporter. The implications of this discovery and the potential for novel therapies for sleep and psychiatric disorders will be explored. PERFORMANCE MILESTONES Every Project PI must submit a grant application by the end of the second year of funding or before. Outcome: Access to the Office of Grants and Scientific Publications at UAMS was supported by the CTN in order to optimize style and organization. This milestone was met by all investigators without exception. Such applications must be submitted to the Director two months before the deadline to allow internal and/or external reviews prior to submission. Outcome: This milestone was not met, requiring flexibility on the part of the Director and the Mentor, mainly to reduce stress and promote a more nurturing environment. A one month deadline was set. If such an application is not submitted, the Director and the IAC, will work with the Project PI to determine the cause(s) and find solutions…. a timetable will be set up to ensure timely progress, to be monitored by the Director…. the Director and the IAC may decide that funding will be terminated, if the EAC and NCRR also concur will a replacement Project PI be sought. Outcome: We did terminate funding of two investigators due to lack of progress, but did not need to do so in any other case due to our successes in funding. If the application submitted is not funded, a resubmission by the end of the third year of funding will be required. Outcome: This milestone was met by all investigators. If the application is funded, the Project PI will be considered to have “graduated” from the program and will retain access to the Cores, unless the funded grant is in a different area. In that case, the obligations of the Project PI will continue, requiring an additional application by the end of one additional year of funding in order to maintain CTN funding. Outcomes:Project I. We continue to fund Dornhoffer, who received one award and has promising additional results using TMS to cure tinnitus. Project II. We replaced Fann, who left UAMS, with two Pilot Study awardees for the rest of the grant year, Charlesworth, who received funding for a parallel line of research and became Director of the Molecular Biology Core, and Fantegrossi, who will be a Replacement Investigator next year. Project III. Hall received funding* for his Neopain Project, but has become Director of the CoBRE Core Facility and will seek funding for a Center for community based research and education. Kaiser became Replacement Investigator for Project III, and immediately secured R01 support. Project IV. We ceased funding the human component of the spinal cord injury project due to recruitment problems and lack of progress (Kiser), but the animal component (Reese, Yates) keeps publishing and submitting scored applications. Project V. MacNicol has received considerable funding as Co-I, and has applications pending on this Project. Pilot Study Awards: All of the awardees were assigned Mentors in order to expedite their research. Other Investigators: Three other investigators were assigned Mentors and provided support by the CTN Cores. INTRODUCTION • The original aims of the Center for Translational Neuroscience (CTN) included the establishment of: •  a Career Development Program with mentoring and funding for 5 projects and 6 promising investigators without a history of support to make them competitive for independent funding, •  a multi-disciplinary center, a Pilot Study Program, and recruitment of two senior and three junior investigators to build the critical mass of researchers at the CTN, and •  two Core Facilities, Administrative and Experimental, to support research by CTN investigators. • All of these aims were met and exceeded, as described below. CORE FACILITIES NEW GRANTS Core Facilities- The need for flexible and diverse Core Facilities is perhaps greater when performing translational research on clinical populations and parallel studies in animals. The challenge has been to develop Cores that use complementary techniques and preparations. The originally proposed 2 Core Facilities, Administrative and Experimental, were increased gradually such that the Experimental Core was expanded into 1) a Human Electrophysiology Core (P50 evoked potential, reaction time and frontal lobe blood flow measures, including a mobile unit for on-site recordings, along with a satellite facility for spinal reflex testing), an ancillary Animal Electrophysiology Core (P13 evoked potential, reflex testing, and surgical capacity), and 2) an Image Analysis Core (confocal and fluorescence microscopy, freezer and contributed equipment in the form of a cryostat, baths, incubators and hoods for immunocytochemistry) in Year 1. In Year 2, we established 3) a Transcranial Magnetic Stimulation (TMS) Core(in Year 5, we will develop our capacity to use TMS on animals by purchasing equipment for our Animal Electrophysiology Core), and began purchasing equipment for the 4) Molecular Biology Core, which was completed and became operational in Year 3. Also in Year 3, we expanded the Animal Electrophysiology Core to include patch-clamp recordings with image analysis of calcium and voltage-sensitive dyes, and established the 5) Community Based Research and Education Core, which was expanded in Year 4 (partly using a Supplement from NCRR) to include real-time teleconferencing and diagnostic quality imaging equipment for 15 rural hospitals and a central Mediasite facility at Arkansas Childrens Hospital. W have accomplished in a few short years the ability to perform research on molecular, cellular, system, individual and community based research, providing the basis for comprehensively addressing clinical problems form the lab to the bedside (T1) and the clinic to the community (T2). We have become a truly translational neuroscience research hub. 6) The Administrative Core is managed by an experienced administrator, Ms Linda Luster, MS, with >20 years experience in UAMS administration. Accounting, purchasing, payroll, travel, functions, personnel and other matters are efficiently handled with grace and on a timely basis. The highly organized procedures we have developed are now finely honed and productive. New Grants brought into the CTN RecruitsMentored Investigators TOTAL Year Name Amount ($) Name Amount ($) 8/04-7/05 Mennemeier 1 256,960 Mennemeier 2 142,000 Mennemeier 3 15,000 413,960 $413,960 8/05-7/06 Al-Chaer 1 335,362 Al-Chaer 2 400,425 Al-Chaer 3 132,438 Al-Chaer 4 232,648 1,100,873 $1,100,873 8/06-7/07 Hayar 1 1,000,000 Dornhoffer 1 300,000 Hayar 2 150,000 Cole 1 142,900 Cole 2 283,838 Cole 3 15,000 Cole 4 31,481 1,150,000 773,219 $1,923,219 8/07-4/08 Al-Chaer 5 221,550 Aitken 1 50,000 Al-Chaer 6 249,669 Aitken 2 741,000 Al-Chaer 7 1,250,000 Aitken 3 594,642 Mennemeier 100,000 Aitken 4 749,963 Aitken 5 168,000 Charlesworth 1 600,000 Hall 1 1,800,000* Kaiser 1 2,131,535 1,821,219 6,835,140 $8,656,359 Cumulative total 4 years $12,094,411 * Letter of award not yet received METHODS We designed a Career Development Program with an a) Established Mentor Program: identified local established basic and clinician scientists in the areas of expertise of our promising scientists and facilitated their collaboration using Project grants, Pilot Study grants and support at no charge from our Core facilities, including subsidizing technical help and supplies. We assigned established Mentors to our Pilot Study awardees and Core users and expanded our mentorship of promising scientists from an initial 6 to 14 promising investigators; b) Visiting Mentor Program: We invited a retired senior scientist to help mentor one Project for two six-month periods over two years with great success. The majority of these costs were incurred from departmental sources; c) External Speaker Program: A total of 4-5 lectures per year were held. Interspersed with these lectures, Investigators presented their findings to the CTN, and included Bench-to-Bedside seminars in which a clinician and a basic scientist presented an integrated view of the same problem/project; d) Biostatistics and Experimental Design: We established a formal process for experimental design and power analysis in the drafting of grant applications and experiments, as well as advice and participation in reporting and publishing results; e) Grant writing: We used UAMS yearly grant writing workshops and the Department of Neurobiology Grant Strategy Sessions for critiques both in advance of applications and for resubmissions. Oversight by an External Advisory Committee (EAC)- included two COBRE PIs, E. Anderson, MD, PhD (Univ. Oklahoma) and S. Whittemore, PhD (Univ. Louisville), as well as established nationally recognized scientists such as D. Humphrey, PhD (Emory Univ.) and W. Willis, MD, PhD (Univ. Texas Med. Branch), and retired NIH SRA K. Murray, PhD; and an Internal Advisory Committee (IAC)- included the Chairs of the departments involved, Neurobiology (G. Childs), Pediatrics (D. Fiser/R. Jacobs), Physical Medicine & Rehabilitation (K. Means), Otolaryngology (J. Suen), and recently Pharmacology (N. Rusch). Our EAC and IAC were extremely helpful in a number of sensitive areas including funding decisions, granting of faculty positions for Recruits, support for space needs, and in the response to recruitment and retention issues. Conclusions Our progress during the first funding period has been exceptional, having exceeded our aims by mentoring almost three times the number of investigators as initially proposed, establishing three times the number of Cores originally envisioned, and securing three times the amount of extramural support estimated. The numbers of articles or chapters published (>120), abstracts or presentations done (>150), and grants submitted and funded by Investigators, Recruits and other faculty supported by the CTN are increasing in number and success rate. We have learned as much as we have taught and are having a dramatic impact in the careers of our young scientists as well as our seasoned Mentors, and are changing the way our research is disseminated and applied to improve the health of our citizens. We now know better how to mentor and execute our charge more efficiently. We believe we can become a model national system for translational research, given continuing support from our previous reviewers, who can feel proud of our accomplishments to date, and from our current reviewers, who can be assured of the great potential the future holds for the CTN and its promising investigators. S SUPPORT NCRR Grant RR020146 to the Center for Translational Neuroscience