Bone marrow dynamics and inflammatory remodeling in CKD progression

Aging and diabetes are among the most prevalent and burdensome chronic conditions worldwide, each contributing significantly to multi-organ dysfunction and mortality. A key shared feature of both conditions is chronic low-grade inflammation, termed “inflammaging” in aging and “metainflammation” in diabetes, that drives immune dysregulation and accelerates disease progression, including the development of chronic kidney disease (CKD). However, how systemic inflammation orchestrates immune dysfunction and leads to organ damage, particularly through the bone marrow (BM), the central hub of hematopoiesis and immune regulation, remains poorly understood. Emerging evidence shows that bone marrow immune cells undergo dynamic reprogramming in response to inflammatory conditions, influencing systemic immunity and peripheral organ health. Our recent findings highlight TNFa as a key amplifier in this process, sustaining inflammation through a self-reinforcing feedback loop. Although the bone marrow is increasingly recognized as a causal and modifiable driver of chronic disease pathogenesis, it remains underappreciated. Most studies rely on single-cell RNA sequencing of isolated cells or bone marrow transplantation, both of which disrupt the native architecture and niche interactions critical for immune regulation. This proposal addresses these challenges by leveraging state-of-the-art 3D spatial transcriptomics to map the intact bone marrow architecture at single-cell resolution, preserving the spatial context of immune-niche interactions. In Specific Aim 1, we will define the 3D spatiotemporal remodeling of the bone marrow in aging- and diabetes-associated CKD. In Specific Aim 2, we will identify and characterize marrow-resident TNFa-producing immune cells using longitudinal in vivo imaging in transgenic fish models and validate findings in murine models. In Specific Aim 3, we will determine whether reprogrammed inflammatory cells derived from the bone marrow migrate to the kidney and contribute to tissue injury through interactions with kidney-resident immune and non-immune cells. This study will provide the first integrated, systems-level map of bone marrow remodeling during chronic inflammation and uncover novel upstream mechanisms linking bone marrow dysfunction to kidney injury. By identifying critical inflammatory mediators and cellular interactions, this work has the potential to reveal new therapeutic targets for preventing or reversing aging- and diabetes-associated inflammaging and metainflammation, ultimately preventing multi-organ dysfunction, including CKD.