Elucidating the molecular and mechanistic role of CILP1 in reverse remodeling in the context of advanced heart failure

Project: Research


  • Linda Berg Luecke (PI)


Heart failure is a clinical syndrome defined by the heart's inability to adequately perfuse the human body. Approximately 10% of heart failure patients will not respond to medical therapy and worsen to develop advanced heart failure. The only definitive treatment for advanced heart failure is heart transplantation, but mechanical circulatory support is increasingly utilized as bridge-to-transplant therapy. While circulatory support contributes to improved cardiac structure and function, known as reverse remodeling, little is known regarding cell-type specific mechanisms and functions that occur during this treatment. Within the heart, cardiac fibroblasts are critical in sustaining normal cardiac function and their pathological activation during heart failure contributes to cardiac remodeling. Our preliminary studies have identified cartilage intermediate layer protein 1 (CILP1), in cardiac fibroblasts from non-failing hearts and hearts from advanced heart failure patients that received circulatory support. However, CILP1 was not detected in advanced heart failure patients that had not received circulatory support, suggesting that CILP1 levels are modulated by heart failure and circulatory support. Prior research has suggested that full-length CILP1 is cleaved into N- and C-terminal fragments, which have been implicated as anti-fibrotic agents. However, questions concerning the specific molecular species of CILP1 that are present and active within advanced heart failure remain unanswered. The proposed studies seek to precisely determine the molecular species of CILP1 that are modulated by advanced heart failure and circulatory support. The work will be carried out in two Aims. Aim 1 will use mass spectrometry approaches to determine whether protein abundance of CILP1 is modulated in reverse remodeling and advanced heart failure. Aim 2 will use pull-down assays and flow cytometry to determine the mechanistic link between binding partners of CILP1 and cardiac fibroblast activation in reverse remodeling and advanced heart failure. The significance of this proposal lies within the fundamental mechanistic questions that will be answered regarding the role of CILP1 in cardiac fibroblasts of failing hearts and questions regarding the potential utility of CILP1 as a therapeutic target or informative marker to study reverse remodeling, currently major challenges in the clinical care of advanced heart failure patients.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35200049
Effective start/end date01/01/202006/30/2022