The overall goal of our project is to address this challenge by studying the role of the macrophage in APOL1-mediated kidney disease. Macrophages are key modulators of tissue homeostasis and injury response, and disruption of their normal function contributes to the development of complex diseases, including different types of CKD. Because risk-variant APOL1 localizes predominantly to the endoplasmic reticulum (ER), it may interact with ER stress pathways that alter inflammatory signaling and macrophage phenotype. Therefore, we hypothesize that risk-variant APOL1 promotes proinflammatory macrophage activation through dysregulated ER stress responses, predisposing the kidney to injury and fibrosis. To test this hypothesis, we are leveraging human cellular model systems, including genome-edited induced pluripotent stem cells, and transgenic mouse models. This proposal aims to (1) delineate in human cellular studies how APOL1 risk variants promote macrophage inflammation from ER stress and (2) investigate in vivo how macrophage ER stress enhanced by APOL1 risk variants modulate proteinuric kidney injury. Completion of the proposed aims will generate crucial data for understanding the molecular underpinnings of how macrophages contribute to APOL1-mediated kidney disease and identify potential novel therapeutic strategies to prevent and treat this disease.
|Effective start/end date||5/20/22 → 3/31/27|
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK131521-02)
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