Nephritis is a common and serious manifestation of Systemic Lupus Erythematosus for which there is no adequate therapy. Some patients will exhibit a response to current immunosuppressive regimens while others will not; all are at risk for on and off target toxicities. The current proposal is to apply new technologies for high resolution analyses of gene expression and immunophenotype to kidney, blood and urine of lupus patients with active nephritis in order to develop a better understanding of disease pathogenesis and tissue injury, and stratify patients with respect to therapeutic response for more informed clinical decision making. We will explore blood and urine for less invasive surrogate markers for kidney inflammation. Our plan relies of optimization of analytic approaches, informed choice of cellular subpopulations to analyze, followed by two small studies to refine and validate the approach. In the first, we will study kidneys, blood and urine o 20 patients at a time of renal flare in order to dissect patterns of inflammation. In the second we will study cellular subsets in blood of 40 patients who were part of a clinical trial of lupus nephritis to understand changes from baseline profiles of gene expression and function response in those who experienced a full clinical response to therapy and those who failed to respond. Finally, we will use the information from these studies to design a large scale longitudinal study of patients with lupus nephritis. This unbiased re-examination of this unmet medical challenge should identify novel therapeutic targets, inform the generation of new models of disease, and lead to predictors of response that can then be validated in clinical trials We have unique technology resources and a powerful consortium of clinical investigators in the newly established Lupus Nephritis Trials Network that includes: (i) the infrastructure and expertise for clinical study implementation; (ii) protocols and consents for acquisition of blood, urine, and biopsy specimens; and (3) scalability to move from phase 0 and 1 to phase 2 at the appropriate time.

Public Health Relevance

This is a proposal to use state-of-the-art gene expression profiling and immunophenotyping of kidney, blood and urine of individuals with lupus nephritis to better understand disease pathogens. Insights from this study may lead to more therapeutic targets and better stratification of patients for clinical decision making.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
3UH2AR067688-04S1
Application #
9542608
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Serrate-Sztein, Susana
Project Start
2014-09-24
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Der, Evan; Ranabothu, Saritha; Suryawanshi, Hemant et al. (2017) Single cell RNA sequencing to dissect the molecular heterogeneity in lupus nephritis. JCI Insight 2: