Monica J. Carson, PhD - US grants

DESCRIPTION (From the applicant's abstract): Microglia have been implicated as key players in the inflammatory responses to many degenerative brain pathologies, including AIDS dementia, trauma, abscess, focal eschemia, EAE, MS and Alzheimer's disease. The information presently available about microglia is incomplete. Our hypothesis is that microglia may arise from the differentiation of stem cells that also give rise to other myeloid cells. However, the roles played by differentiated microglia in vivo are different from macrophages and are determined in major part by the proteins that are expressed after their differentiation. One of the major obstacles to defining microglial function in vivo during pathological events is the lack of reagents that definitively distinguish microglia from macrophages. We propose to identify novel and known microglial proteins that distinguish microglia from macrophages and/or that are induced by CNS inflammation. We will compare the patterns of expression of these mRNAs in both in vitro models in which microglial function is well-defined and in vivo models of inflammation with acute, chronic and relapsing phenotypes. Cumulatively, these studies will (1) allow us to recognize ensembles of proteins that are active in different neuropathologies, (2) define microglial in terms of unique patterns of gene expression that include not only expression of novel molecules, but a cell type specific regulation of these molecules, and (3) because this definition is molecularly based, these studies will generate a set of readily portable reagents for others studying microglial function in vivo and in vitro.

[unreadable] DESCRIPTION (provided by applicant): Microglial activation is a prominent feature of numerous neuropathologies including Alzheimer's disease, multiple sclerosis and stroke. As the tissue macrophage of the CNS, microglia have the potential to regulate and be regulated by cells of the CNS and by CNS-infiltrating immune cells. The exquisite sensitivity of microglia to these signals, coupled with their ability to develop a broad range of effector functions allows the CNS to tailor microglial function for specific physiological needs. As yet the mechanisms by which the CNS and the immune system regulate microglial function are incompletely defined. We have recently discovered that subsets of microglia in the healthy murine CNS constitutively express Triggering Receptors Expressed on Myeloid cells-2 (TREM-2), illustrating microglial heterogeneity not only between brain regions, but also even within a single brain region. While microglial expression of TREM-2 is repressed by LPS, expression was dramatically upregulated in transgenic mice overexpressing beta-amyloid but only in those cells immediately surrounding amyloid plaques. Conversely, while unactivated microglia do not express TREM-1, LPS-activated microglia do. Functionally, these receptors have the potential to regulate critical states of microglial activation and differentiation in potentially opposing directions. Our preliminary studies suggest microglia express additional and perhaps CNS-specific forms of these receptors. Some of these forms may have the potential to serve as "decoy" receptors for the as yet unknown ligand(s) for these receptors. Here we propose 1) to clone, identify and generate antisera specific for each form, in order to characterize TREM expression in healthy and inflamed CNS; 2) dissect the potential intracellular signaling pathways triggered by these receptors; and 3) define the functional consequences of TREM expression by microglia. Our analysis will focus on signals and outcomes relevant for bacterial signals, CNS autoimmunity, and Alzheimer's disease. [unreadable] [unreadable]

Abstract (30 lines max): The purpose of this R13 submission is to request funds for trainees and for a limited number of junior investigator speakers and those from groups traditionally underrepresented in the STEM fields to participate in the 2018 FASEB summer research conference: Translational Neuroimmunology: from mechanisms to therapeutics. This will be the 14th FASEB Neuroimmunology conference and will be held at the Village Conference Center in Snowmass, CO from July 8-13, 2018. The last FASEB meeting was also held in Big Sky, MT in 2016, where Dr. Thomas Lane was elected as co-chair to work with Dr. Monica Carson who was the 2016 co-chair and is the 2018 chair. The 2018 conference is distinct in its bringing together a diverse group of neuroscientists, immunologists, microbiologists, toxicologists, vascular biologists, clinicians, translational and basic research scientists at a venue and with a program fostering interaction between individuals with different expertise and at different career stage. Previous evaluations have ranked this conference highly for ample presentation and discussion time, for high impact speakers who remain for the duration of the conference, oral presentations, selection of abstracts from junior scientists and graduate trainees for short platform presentations, well attended poster sessions, time for free and open discussions between speakers and attendees aimed at fostering new and ongoing collaborations. The 2018 program is aimed not only at defining the contributions of neuro-immune interactions in CNS health and disease. It also seeks to explore the opportunities and challenges for harnessing neuroimmune interactions as therapies for classic neurologic and neurodegenerative diseases including neurodevelopmental disorders, TBI, spinal cord injury, stroke, epilepsy, multiple sclerosis, Alzheimer?s and Parkinson?s disease. In response to evaluation requests from trainees and junior investigators attending the 2016 conference, new this year are addition of two workshops discussing pragmatic issues and careers aimed at bridging the well-known ?valley of death? between seminal research discoveries and development of approved and available therapies. In aggregate, the specific goals of this conference are to: 1) provide a forum for the presentation of unpublished, cutting-edge research by investigators from diverse fields applicable to neuroimmune regulation of CNS health and disease; 2) provide forums for both formal and informal discussions on how results from complementary fields advance our understanding of how neuroimmune interactions support CNS function and health lifelong and can be modified by genetics, pathogens, toxicants and behavior to drive disease pathology, 3) ensure development and integration of young investigators from diverse backgrounds and those traditionally under-represented in these fields into the broader research community in a meaningful and interactive way. Altogether, attendees will enjoy a multidisciplinary group of researchers not found together at other specialized conferences and will benefit from the focus on the opportunities & challenges in translating research discoveries to therapies. ! !

Investigator Development Core: Abstract The purpose of the investigator development core (IDC) is to train a diverse workforce of individuals able to effectively tackle transdisciplinary problems in health disparities and inequalities as collaborative teams while still serving as leaders in their own disciplines. To fulfill this purpose, this core will provide individualized mentorship teams for trainees, provide pilot grant funding to launch trainee?s progression toward independence, oversee development and completion of trainee?s individual development plans and project progression to the point of publication and submission of applications to external funding agencies. The IDC will utilize the Big, Feasible and Fundable (BFF) seminar series in Health Disparities and the Administrative Core?s Interdisciplinary Research Workgroups (IRWG) activities as pipelines to recruit and identify trainees as well as essential tools to facilitate and assess trainee acquisition of essential skills in communicating and collaborating across disparate disciplines. By being open to both U54 center members as well as those interested in exploring collaborative opportunities, the BFF will also serve as the home base linking and fostering community between diverse multiple transdisciplinary teams. Our proposed program has the advantage of providing benefit not only to individuals selected as trainees but also to the larger campus community of potential trainees as well as for current and potential collaborators, mentors and U54 participants.