This revised proposal gives equal attention to the priorities of mentoring and the research plan. The research plan is directed to understanding the anatomic and functional aspects of chemokine receptor expression in the lesions of multiple sclerosis (MS) a disease, which is the most prevalent primary neurological cause of disability in the United States. Our data show that chemokine receptors are selectively expressed by infiltrating cells (monocytes and T cells) in MS lesions, with different patterns, that vary according to lesion character. These findings prompted us to address the following questions: First, how does chemokine receptor expression correlate with MRI-characteristics of MS lesions, as determined in a unique series of tissues subjected to MRI/pathological correlations? Second, is there heterogeneous expression of chemokines and their receptors, in different lesions of MS within a single brain? We will examine these questions by immunohistochemical studies of tissue sections from MS patients and appropriate controls. We will test hypotheses derived from these studies using functional analysis, using a novel in vitro model of the blood brain barrier (BBB). The plan entails new directions for the PI, who will become familiar with imaging research techniques. Further, in the effort to identify biomarkers that indicate which pathological patterns are represented by MRI lesion characteristics in vivo, will require familiarity with a diverse range of clinical research methods. Together, these new directions necessitate a period of intense research focus under the K24 Award. This program will also allow for expanded mentoring activities, for beginning clinician investigators. The mentoring component of this proposal includes progression from descriptive immunohistochemical analysis of MS tissue sections, through hypothesis generation based on the descriptive data, culminating in hypothesis testing, using the BBB model system. The mentorship will be enriched by participation of an advisory team including other clinical and basic researchers as well as biostatistical support. Formal classwork and informal guidance are integrated in the mentoring plan, which will result in development of clinician-scientists who are enabled to use cutting edge research techniques to elucidate human disease.
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