Claudia F. Lucchinetti - US grants

multiple sclerosis; immunopathology; biological polymorphism; pathologic process; therapy design /development; disease /disorder etiology; virus diseases; myelinopathy; oligodendroglia; clinical research; nuclear magnetic resonance spectroscopy; human subject; magnetic resonance imaging;

[unreadable] DESCRIPTION (provided by applicant): Our preliminary studies suggest there is intra-individual homogeneity within both early and chronic MS lesions with respect to pathologic measures of inflammation, dominant immune effector mechanisms of active demyelination, and extent of tissue injury and repair. Evidence of intra- individual pathological homogeneity may reflect genetic variation in loci controlling lesion formation. We propose to collect and pathologically phenotype a large sample of MS lesions in order to examine both the complex relationships between inflammation, demyelination, remyelination, and axonal injury in both early and chronic MS lesions, as well as investigate the relationship of demographic and clinical variables with these pathologic outcomes. In addition, we will assess the degree of intra-individual homogeneity for these well defined specific histo- and immunopathological outcomes in order to validate our preliminary observations of intra-individual homogeneity, and more accurately establish the number of cases within each of the respective pathological phenotypes available for future genetic study. We aim to establish a reliable and statistically robust MS Tissue-DNA Databank which will use pathology as a novel intermediate outcome for future genetic-association studies The proposed studies will yield a tremendous resource of patient material having both detailed and quantitative pathologic analyses and DNA, and will provide the framework for an efficient and cost-effective transition from discovery of chromosomal regions or candidate genes of interest in genome-wide linkage, population-association and tissue microarray studies, to detailed clinical-pathologic analysis in order to determine pathogenic relevance. By stratifying patients based on specific pathological features, we will increase the likelihood of identifying potential genetic contributions common to each category. Furthermore, there are pragmatic reasons for supporting additional research into MS pathology and genetics. A more fundamental understanding of the variable pathological and genetic factors involved in MS lesion evolution will not only provide additional pathogenetic insights into MS, but will lead to improved determination of long term prognoses, as well as impact the selection of current, and design of future, treatment approaches tailored to the patient. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) research has largely focused on white matter (WM) pathology, however recent studies on MS tissue from late stage disease suggest cortical damage is an important correlate of disability;is driven by organized late meningeal inflammation;and cortical demyelinated (CDM) lesions lack macrophage and lymphocytic infiltrates. Since actively demyelinating cortical lesions are sparse at this late stage, it is difficult to characterize the mechanisms behind the cortical damage. Our prior funded research focused on early biopsy and autopsy MS cases and revealed CDM occurs early;can be inflammatory;and meningeal inflammation is prominent. These findings correlate well with recent MRI reports demonstrating cortical damage in early MS. In concert with recent experimental reports, we propose novel hypotheses about the role(s) of meningeal inflammation and cortical pathology in promoting the MS disease process. We hypothesize cortical pathology can be an early event in MS, and is related to early meningeal inflammation. We will define the frequency and extent of CDM in an early MS cohort and determine its relationship to meningeal aggregates in early and late disease. We propose contact between myelin-specific T cells from the periphery and meningeal antigen presenting cells (APCs) occurs early in the subarachnoid space (SAS);expands myelin-specific T cells;and generates new memory cells which traffic to cervical lymph nodes (LN) via CSF, promoting subpial DM. We will characterize T cells and APCs in the SAS and define the nature of T cell-APC contacts. Our preliminary data demonstrates myelin laden macrophages in both SAS and CDM lesions. We hypothesize CDM generates macrophage/dendritic cells laden with myelin antigen and bearing trafficking determinants indicative of capability to access lymph nodes via CSF and perpetuate (auto)immunity. We aim to characterize if these cells have a mature dendritic phenotype. We have identified meningeal inflammation during early MS. We propose these early meningeal aggregates set the stage for long-lasting lymphoid aggregates in the SAS which drive ongoing cortical damage in progressive MS. We will characterize these infiltrates for indications of early lymphoid aggregate character. We find T-cell inflammation may be prominent in early CDM, but more transient than WM lesions. We propose this transient inflammation relates to expression of LN trafficking chemokines on cortical T cells which facilitate their rapid exit. We will examine T cells in CDM and WM lesions for these trafficking determinants. We propose CDM and inflammation mediate cortical injury, and that subpial DM will proceed by mechanisms distinct from those observed in WM based lesions. We will characterize and define relationships between inflammatory and neurodegenerative pathology in cortical lesions, and compare CDM and WM lesions with respect to targets and mechanisms of DM. These experiments addressing novel hypotheses;provide a rare opportunity to assess pathogenic relevance of animal data to MS pathology;build upon our unique well phenotyped tissue resources;and carry the potential to discern new therapeutic targets. PUBLIC HEALTH RELEVANCE: Most treatment and research efforts in MS have focused on white matter lesions, however recent studies indicate evidence for widespread demyelination of the brain surface called the cortex, which is thought to be an important cause of progressive disability. The current proposal studies cortical lesions from MS patients with early disease, in order to better understand the mechanisms underlying the tissue damage, and how it relates to white matter MS lesions. Studies examining the causes of cortical demyelination in early MS and its relationship to white matter pathology are needed in order to better understand the pathogenesis of disease initiation, evolution, and progression, in the hope of ultimately developing more effective therapeutic strategies for MS patients.

Contact PD/PI: Khosla, Sundeep Clinical and Translational Science (CTS) has been a fundamental and highly valued element of Mayo Clinic since its founding, and Mayo Clinic's mission ?to provide the best care to every patient every day through integrated clinical practice, education, and research? has always aligned well with the NCATS mission. Mayo Clinic is an integrated academic group practice with major sites in Minnesota, Arizona, and Florida; a large community Health System (MCHS) in Minnesota, Wisconsin, and Iowa; and an affiliated national ?Care Network? (MCCN). Thus, the Mayo Clinic Center for Clinical and Translational Science (CCaTS) is of national scope. MCHS and MCCN provide unique laboratories for late-stage dissemination and implementation research as well as for the conduct of high-priority clinical trials in community health care organizations. Mayo Clinic is also leading both a PCORI CDRN and a PPRN. These widespread connections, and programs that span the translational spectrum, position Mayo Clinic CCaTS to become a true ?hub? for CTS. The present application builds on key accomplishments over the previous 5 years in each of the major areas relevant to the NCATS mission. Mayo CCaTS has mature, innovative programs in workforce development for all members of CTS teams and is diversifying them through online and experiential learning. Incentivizing Team Science has always been part of the institutional culture at Mayo, and we are continuing to build on that strength. Given its role, particularly in Rochester, as a major local and regional provider of health care, community engagement has also been a priority for Mayo Clinic, and a range of methods for bidirectional engagement are proposed. Advances in informatics are also enabling us to connect with new and diverse patient populations. Thus, in light of our institutional traditions and accomplishments over the past 5 years, we believe we are uniquely positioned to accomplish our Specific Aims: Aim 1. Train and maintain an outstanding multidisciplinary CTS workforce, including the entire spectrum of individuals involved in CTS; Aim 2. Eliminate barriers to the work of translation by streamlining methods and processes, including improved and innovative informatics tools, completing the transformation of Mayo's clinical trial process, and accelerating the implementation of trial results and other discoveries to improve patient care; Aim 3. Engage and incorporate a range of diverse stakeholders as active participants in CCaTS, both in leadership roles and in specific research projects, to improve the process of translation and the delivery of health care, promoting community engagement in research among our Mayo workforce and engaging our local and national communities using both traditional and innovative approaches; and Aim 4. Expand, strengthen, and streamline our regional and national collaborations in all aspects of CTS and education, connecting with our regional and national partners, as well as with the CTSA Consortium, to achieve the ultimate goal of NCATS to improve patient care and human health.