Yale Center for X-Linked Hypophosphatemia

 

PILOT AND FEASIBILITY PROGRAM

The Yale Center for X-Linked Hypophosphatemia launched its P and F program in early 2008 with a request for applications.  We received four commendable applications for this new program, and after peer review by 8 national experts, selected the top three scoring proposals for funding.  The awardees will receive up to two years of funding for their project under the NIAMS CORT funding mechanism. The projects bring 2 investigators with other established interests to the phosphate field, and allow a young investigator with  demonstrated expertise in the FGFR field to pursue a unique area of disease mechanism in a rare form of clinical hypophosphatemia.  The projects all have a clinical relevance and fit the Center’s translational mission. The projects are outlined below:

Dr. Veraragavan Eswarakumar’s project, “Use of an animal model of Epidermal Nevus Syndrome to understand the mechanism of FGFR signaling in renal phosphate wasting syndromes” will focus on mechanism of disease a rare phosphate wasting syndrome that has been associated with FGF receptor disfunction. Dr. Eswarakumar notes, “Because ENS is due to mosaicism resulting from a postzygotic mutation of the FGFR3 gene, we hypothesize that cells other than keratinocytes harbor the mutation and thus contribute to the skeletal abnormalities and phosphate wasting observed in ENS patients.  Our goal is to create an animal model of ENS by introducing the lethal FGFR3-R248C mutation into the mouse germline using a loxP-flanked stop sequence to overcome prenatal lethality and then selectively activating the mutation in specific tissues including skin, bone, and kidney.  Identifying tissues that harbor the FGFR3-R248C mutant receptor will contribute to an improved understanding of the mechanism of FGFR signaling in phosphate homeostasis and ENS.”

Dr. Carolyn Macica’s project,  “A Study of Enthesopathy in X-Linked Hypophosphatemia,”  is focused on a particularly debilitating complication of XLH in later years. She will study the progression and pathogenisis underlying the paradoxical calcification of tendon and ligament insertion sites. Dr. Macica states: “The formation of enthesophytes will be our focus, with a major emphasis on characterizing the cellular changes that occur in enthesophyte formation using the murine model of XLH, Hyp mice. We have found that mineralization, while thought to originate from the bone, is actually due to both an expansion of fibrocartilage cells that express the FGFR3 receptor and an increase in alkaline phosphatase activity.  Our goal is to study the role of elevated circulating levels of FGF23 in fibrocartilage expansion using FGFR3 knockout mice on the Hyp background and in Dmp1 knockout mice, another model of osteomalacia characterized by elevated FGF23 levels, independent of the Phex mutation. We have evidence that an increase in chondrocyte-derived alkaline phosphatase is likely involved in the mineralization of both entheses and in articular cartilage. We also aim to better characterize the dysregulation of alkaline phosphatase specific to cells of chondrocyte (vs. osteoblast) origin.”

Our third Pilot awardee is Dr. Gerald Shulman, a well-known clinical investigator in the field of carbohydrate metabolism and diabetes. His project “In Vivo 31P NMR Studies of Intracellular Phosphate, Mitochondrial and Whole Body Energy Metabolism in Hypophosphatemic Normal and Hyp-/- Mice” will examine the role of intracellular phosphate , as pertains to energy metabolism. Dr. Shulman notes: “In preliminary studies we have found that dietary Pi-deprivation in normal mice results in severe hypophosphatemia and a 50% reduction in skeletal muscle ATP synthesis as measured by in vivo 31P-MRS saturation transfer methods. In addition, these mice exhibit reduced whole body energy expenditure, activity, and oxygen consumption. We will examine intracellular phosphate metabolism, mitochondrial ATP synthesis and whole body energy metabolism in hypophosphatemic and euphosphatemic Hyp mice using the same techniques. It is anticipated that the results from these studies will provide important new insights into the role of intracellular phosphate metabolism on the regulation of mitochondrial and whole body energy metabolism under normal physiological conditions as well as provide new insights into intracellular phosphate metabolism in patients with X-linked hypophosphatemia.”

The YC-XLH is delighted to have Drs. Eswarakumar, Macica and Shulman as pilot project awardees, and will be enthusiastically following the progress of their research in the next few years.