# Gene Transcription in SLE

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $597,513

## Abstract

The multitude of mechanisms that lead to general break of tolerance and organ pathology in
patients with systemic lupus erythematosus (SLE) have challenged both basic immunologists
and translational researchers. Our studies in people and mice with SLE have documented
molecular mechanisms that account for the opposite production of interleukin 2 and interleukin
17, both of which are being exploited in clinical trials to treat people with SLE. We found that
the transcription factor cAMP response element modulator, which accounts for the opposite
transcription of the genes encoding for these two cytokines, controls also the expression of
ADAM9, a disintegrin metalloproteinase. Early information indicates that ADAM9, a new comer
in the field of autoimmunity, controls peripheral autoimmunity and organ inflammation. ADAM9
is expressed at increased levels in peripheral blood lymphocytes, lymphocytes entering tissues
and tissue resident cells. We have built the hypothesis that ADAM9 controls systemic
autoimmunity and organ damage through distinct molecular mechanisms. Using human cells
and tissues and a series of newly constructed mice and novel technology to alter gene
expression by delivering gRNA in a cell-targeted manner, we will establish that ADMA9 controls
autoimmunity in SLE, that tissue hypoxia further promotes the expression of ADAM9 by cells
entering tissues and its expression by tissue resident cells and how ADAM9 is involved in the
aberrant tissue growth factor beta cell signaling in SLE T cells. Through this work
metaloproteinases are introduced in the field of autoimmunity for the first time. The value of the
work is based on the parallel use of human cells and tissues, novel engineered mice and
cutting-edge approaches to alter the expression of molecules involved in the pathogenesis of
SLE in a highly precise manner.

## Key facts

- **NIH application ID:** 10866531
- **Project number:** 5R01AI049954-23
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** George C Tsokos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,513
- **Award type:** 5
- **Project period:** 2002-04-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866531

## Citation

> US National Institutes of Health, RePORTER application 10866531, Gene Transcription in SLE (5R01AI049954-23). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10866531. Licensed CC0.

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