The purpose of Dr. Jennifer Iudicello's K23 application is to provide focused training and mentoring in the neurobiological aspects of methamphetamine (METH) addiction and HIV disease that builds on her strong academic foundation in the neurocognitive and functional consequences of addictions and neuroAIDS in service of her long-term goals as an independent, transdisciplinary patient-oriented investigator. The proposed training, knowledge, and research experience will promote her development into an independent investigator capable of bridging laboratory neurobiological discoveries with their clinical expression and real-world impact among persons living with METH addiction and HIV disease. This work is of considerable
because both of these conditions are prevalent, commonly co-occur, and exert adverse independent and combined effects on brain structure and function. The combined effects on brain structure and function is of critical clinical importance since neurocognitive impairment has been linked to poorer functional and health outcomes. Biomarkers of nervous system injury may be useful tools for understanding the neuropathological processes underlying METH- and HIV-associated neurocognitive and functional decline and could provide valuable insights for future drug development. This K23 application proposes to determine the associations between a unique panel of biomarkers in METH and HIV specifically chosen to reflect the structural and functional integrity of essential components of the blood-brain barrier (BBB) - including endothelial cell adhesion molecules, tight junction proteins (TJPs), and basement membrane proteins - and METH- and HIV associated neurocognitive and functional decline. The focused training and research goals of this K23 fill a critical gap in Dr. Iudicello's past training by enabling her to: 1) Gain knowledge and expertise in METH- and HIV-associated neurobiology, with a particular emphasis on the BBB; 2) Gain both practical hands-on (e.g., biomarker assay development) and analytic experience that will allow for proficiency in biomarker data collection, analysis, and interpretation; 3) Apply the knowledge and skills acquired through applied and didactic training by conducting independent research on the associations between biomarkers of BBB injury and METH- and HIV-associated neurocognitive and functional declines, which will subsequently lead to new R21 and R01 applications; and 4) Disseminate research in order to advance the science and practice of addictions and neuroAIDS, promote research collaborations, and stimulate the development of innovative research ideas and future directions. To facilitate the successful completion of her training objectives and career goals, Dr. Iudicello has assembled an accomplished, multidisciplinary team of mentors with expertise in all areas of research relevant to this project, including biomarkers and infectious diseases (Primary Mentor, Dr. Scott Letendre), neurovascular injury (Co-Mentor, Dr. Ronald J. Ellis), neuropsychology and functional outcomes (Co-Mentor, Dr. Robert K. Heaton), neuroscience and addictions (Co-Mentor, Dr. Igor Grant), advanced statistics (Co-Mentor, Dr. Florin Vaida), and biomarkers specific to BBB injury in METH and HIV (Consultant, Dr. Yuri Persidsky). When combined with well-established resources and strong infrastructure of the UCSD HIV Neurobehavioral Research Program (HNRP) and the Translational Methamphetamine AIDS Research Center (TMARC), this K23 award will provide critical support that will allow Dr. Iudicello to attain her short- and long-term goals of becoming an influential independent clinical researcher with transdisciplinary expertise that will help advance the field of addictions and neuroAIDS and improve the lives of individuals affected by these conditions. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) is one of the most commonly abused drugs in HIV disease, and both METH and HIV have significant adverse effects on the vasculature of the brain, including injury to the barrier that separates the brain from circulating blood (i.e., the blood-brain barrier, or BBB). Identifying and measuring a panel of biomarkers specific to BBB injury is an innovative approach to understanding the neuropathological processes (e.g., vascular disease) that may play a critical role in the development and persistence of METH- and HIV-associated neurocognitive impairment and real-world outcomes, such as employment. Such transdisciplinary clinical research may inform the development of more effective pharmacological treatment approaches aimed at ameliorating neurocognitive impairment and improving overall quality of life among persons living with METH and HIV.
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