Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY Research: Lupus nephritis (LN) is a serious complication occurring in more than 50% of patients with systemic lupus erythematosus (SLE) and dramatically worsens the mortality in this population. Despite the significant morbidity associated with LN, we lack biomarkers, specific medications, and a clear understanding of its pathogenesis. The ability to accurately identify SLE patients likely to develop LN could shift the current management paradigm from treatment to prevention and facilitate consideration of aggressive therapy to attenuate autoimmunity prior to kidney involvement. My preliminary data show that IgG from patients with LN is glycosylated differently from SLE patients without nephritis and when it enters podocytes it binds a lectin to initiate signaling processes which involves the upregulation of calcium/calmodulin kinase IV (CaMK4) leading to injury. Inhibiting CaMK4 in podocytes only, prevents immune complex deposition and nephritis in lupus prone mice. The objective of this research proposal is to test the hypothesis that aberrantly glycosylated IgG injures podocytes by upregulating CaMK4 in patients with LN through binding to the lectin CLEC7A in three sets of complementary experiments. In the first the glycosylation pattern of IgG will be characterized in patients with LN and control subjects including SLE patients without LN. In the second the signaling cascade that is triggered by IgG in podocytes will be defined. In the third, a pilot prospective study will be performed to determine whether measurement of CaMK4 levels in urine podocytes and in cultured podocytes exposed to serum IgG can reliably identify patients with LN. Successful completion of the proposed work will reveal new treatment and diagnostic tools to identify individuals with SLE destined to develop LN and follow response to treatment. Candidate Career Goals: My career goal is to become a successful academic physician-scientist leading a translational research program on the pathophysiology of immune complex-mediated kidney disease with a focus on lupus nephritis. To achieve this, I will work with experts in glycomics, immunology, pathology, SLE, nephrology and scientific innovation. The studies outlined in this application will be critical to obtain the training, knowledge, and expertise needed to successfully establish an independent translational research program integrating glycomics and immunology with kidney pathology and hold a tenure-track physician-scientist position in academic nephrology. The K99 phase will be performed under the mentorship of Dr. George Tsokos who is a known leader in the field of SLE, with guidance from an interdisciplinary Scientific Advisory Committee composed of experts in each of these areas specifically geared towards training in functional glycomics and advanced immunology. With this training in hand, the proposed R00 phase research will then establish lectin- glycan recognition systems and their signaling in lupus nephritis.
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