Dr. Leif Oxburgh is a principal investigator in the Center for Regenerative Medicine at the Maine Medical Center Research Institute. He received his DVM and PhD in Virology from the Swedish University of Agricultural Sciences. He joined MMCRI in 2004 after leaving a Research Fellow position at the Department of Molecular and Cellular Biology at Harvard University.

Research interests

Acute kidney injury is a relatively common and life threatening consequence of cardiac arrest, hemorrhage, and sepsis as well as a side-effect of chemotherapy with platinum compounds. As there are no known curative therapies for this condition, treatment is generally supportive, utilizing the intrinsic regenerative capacity of the organ. Signaling by Bone Morphogenetic Proteins (BMP) is known to both protect the kidney from injury, and to accelerate its recovery. The focus of our work is to understand how BMPs promote growth of embryonic and adult kidney cells, with the long-term goal of identifying cellular processes that might be targeted to encourage regeneration following injury.

BMP signaling in embryonic kidney development

During fetal life the nephrons of the kidney develop from a homogenous mass of a few thousand cells. In order to form the mature organ this cell mass must multiply many-fold whilst simultaneously forming complex, physiologically functional filtering units. The orchestration of this developmental process has been studied in detail since the 1950s, yet the exact signals regulating it remain unknown. Both organ culture studies and gene inactivation in mice have shown that BMP signaling plays a central role in kidney development. In particular, Bmp7 is essential for maintenance of the progenitor cell population that gives rise to the nephron, or functional filtering unit of the kidney. Our studies aim to define the precise mechanisms by which BMP7 promotes growth and survival of these nephron progenitors. Currently, we are testing two concepts: i) BMP7 acts on cells surrounding nephron progenitors, indirectly causing them to maintain their growth and survival, ii) BMP7 triggers proliferation and survival pathways directly in nephron progenitors. We have recently developed both a BMP reporter transgenic mouse strain expressing the beta galactosidase enzyme at sites of active signaling, and a primary cell culture system to test these hypotheses.

BMP signaling in acute kidney injury

Although it is known that the kidney initiates a process of regeneration immediately following injury, signals regulating this process are poorly characterized. Because of its role in maintenance of embryonic nephron progenitors, the BMP pathway is a natural candidate for pro-regenerative signaling in the adult. Indeed, treatment of animals with BMP7 ameliorates acute kidney injury and, importantly, accelerates recovery. However, at present it is unclear whether this is due to the anti-inflammatory effects of BMP7, or to proliferative effects directly on regenerating epithelia. We have strong evidence for the latter, and can show that BMP signaling is highly activate in epithelial cells repopulating regenerating nephrons. A screen comparing healthy and regenerating kidneys has identified a novel BMP antagonist specifically expressed in injury-prone sections of the nephron, which is downregulated immediately following injury. The role of this antagonist in limiting the response of intact nephron epithelia to BMPs, and the cell biological effects of BMPs on regenerating epithelia are actively being studied using cell biological and genetic models.

 

 

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