O sistema do neuropeptídeo Y como um novo alvo terapêutico para o traumatismo cranioencefálico

Traumatic Brain Injury (TBI) stands as a critical public health concern, imposing substantial physical, psychological, and economic burdens globally. Europe alone witnesses approximately 2.5 million new TBI cases each year, leading to over 170,000 deaths and leaving many survivors with long-term disabilities. Despite the high prevalence and substantial burden of TBI, current therapeutic options are primarily supportive, focusing on symptom management and the prevention of secondary injuries rather than addressing the primary injury mechanisms. This gap in therapeutic options underscores the urgent need for targeted interventions that can mitigate the multifaceted effects of TBI, including neuroinflammation, blood-brain barrier (BBB) disruption, and transmigration of immune cells [REF]. Furthermore, the lack of specific diagnostic tests and parameters significantly challenges the management and prognosis of TBI patients. Reliance on conventional imaging and clinical evaluations falls short of providing a comprehensive understanding of the injury severity and progression, hindering personalized treatment approaches and the monitoring of recovery. Given the substantial burden of TBI and the limitations of current therapeutic approaches and patient management, this research project aims to address these unmet needs by: MAIN GOAL: Identify Neuropeptide Y (NPY) as a new therapeutic target against TBI-induced brain damage. GOAL 1: assess the protective effect of the agonist of NPY receptor 2 against hallmarks of TBI, such as brain edema, BBB disruption, immune cells transmigration, and behavior abnormalities. GOAL 2: unravel the molecular mechanism underlying NPY beneficial effect on BBB. GOAL 3: Synthesize and validate novel functionalized chitosan nanoparticles to efficiently and safely deliver NPY receptor agonist into the brain. GOAL 4: discovery of new biomarkers for stratification and monitorization of human TBI patients. For that we defined a pipeline that will establish NPY as a first-in-class therapy for TBI, targeting its neuroprotective properties to mitigate neuroinflammation, BBB disruption, and long-term cognitive decline (Task 1&2); will design and validate innovative chitosan nanoparticles specifically engineered to deliver NPY across BBB, maximizing therapeutic efficacy and minimizing side effects (Task 4); and will identifying novel blood-based biomarkers, to improve patient stratification, prognosis, and treatment personalization (Task 4). By addressing these critical gaps, this project aims to advance our understanding of brain protective mechanisms of NPY, develop targeted drug delivery systems for enhanced therapeutic efficacy, and identify blood-based biomarkers for improved patient stratification and monitoring. Through these endeavors, the project aligns with the UN 2030 Agenda for Sustainable Development by promoting health and well-being, fostering innovation in healthcare, and enhancing the quality of life for individuals affected by TBI. Additionally, the project contributes to regional goals by advancing knowledge and healthcare solutions for a critical public health concern. This project proposes innovative approaches beyond the current state of the art and also fosters interdisciplinary collaboration, leveraging the expertise of a highly skilled team across neuroscience, pharmacology, nanomedicine, and diagnostics, highlighting its potential to make a significant impact on TBI treatment and patient care.