Dr. Mckee received $979, 200 of funding over the next five years for his project “Mineralization mechanisms and osteopontin in bones and health”. Dr. Vachon Presseau received $359,549 of funding for the next three and a half years for his project “Developing and validating biomarkers for chronic pain”.
Mineralization mechanisms and osteopontin in bones and health
Bones and teeth undergo a process called mineralization where small calcium- and phosphate-containing crystals are deposited into a scaffolding of proteins called the extracellular matrix. Protein-mineral interactions define properties of the mineral phase making the tissues strong and hard. Our work is relevant to understanding the decreased mineralization that occurs in the osteomalacia and odontomalacia diseases where bones and teeth are incompletely mineralized, soft and deformable, and prone to buckling called pseudofracturing. The research is also relevant to calcification diseases of normally "soft" tissues (such as the mineralization of blood vessels and heart valves). Compelling evidence indicates that a protein called osteopontin (OPN) controls mineralization in most tissues. Also important is that processing of OPN by enzymes leads to mineralization-inhibiting protein fragments (peptides) with different inhibitory potencies. We investigate how processing of OPN defines a control mechanism affecting biomineralization. Here we propose to examine this possible regulation, guided by the general hypothesis that OPN in bones and teeth, and peptides derived from enzymatic processing of OPN, control mineralization by binding to mineral precursor phases and crystal surfaces in a way that influences the hardening process. We will investigate these mechanisms in cell-free systems in which calcium-phosphate crystals are grown in the presence of OPN/peptides, in cell culture and mouse models of disease, and in humans from small bone biopsy samples and extracted teeth. We will use biochemical measurements, bioimaging microscopies including high-resolution electron and atomic force microscopy and X-ray approaches, and various biophysical methods to characterize tissues, mineral and mineral-protein complexes. Such work should provide insight into keeping bones and teeth strong and healthy, and may suggest ways to treat patients where these tissues are defective.
Developing and validating biomarkers for chronic pain
The cause of chronic pain remains elusive and the development of better diagnostic tools is among the most promising targets for improving pain management. This proposal means to leverage recent advances in artificial intelligence applied to brain imaging data to develop objective biomarkers for chronic pain. Magnetic resonance imaging is a brain imaging method that has been successfully used for decoding thoughts, feelings, and dreams from brain activity. Despite its potential for capturing pain, brain imaging has yet provided clinically useful tools for diagnosis, prognostication, and prediction of chronic pain. The advent of openly available very large datasets provides new opportunities to use artificial intelligence to develop biomarkers for chronic pain. The main objective of this proposal is to develop and validate brain-based biomarkers using data from a large number of individuals and to test the generalization of this marker to another data set. The secondary objective is to test the stability of the biomarkers across contexts and imaging sessions across time. More precisely, we will test if the expression of the biomarker is changing in patients receiving placebo or pharmacological treatment. This will help us determining if our biomarker can predict and/or track pain analgesia following treatments. Furthermore, we will test if our biomarkers can predict the prognostic of chronic pain in subacute back pain individuals one year later. A biomarker for chronic pain would represent an objective measurement of the pathology that can be used for both clinical and research contexts. This would ultimately represent an important advancement for prevention strategies and may ultimately lead to improved chronic pain management as well as a reduction of harms for patients.