Peterson Lab

Mineralization is a process through which an organic substance becomes impregnated by inorganic substances. It is critically important to biology and when disrupted or hyperactivated contributes to wide-ranging effects on human health particularly in aging populations. For example, deficiencies in mineralization contribute to osteoporosis and cancer progression in bone, whereas elevated mineralization contributes to vascular disease such as atherosclerosis and kidney disease. The mechanism of the therapeutic action of the most commonly used drug class for treating several of these conditions, Nitrogenous Bisphosphonates (NBPs), is poorly understood. Through genetic screening we identified several genes whose loss of function led to resistance to the cytotoxic effects of the NBP, Alendronate (Fosamax®). Heretofore, we named these functionally-related genes the Target of BisphOsphonate NitrogEnous (TBONE) pathway. We have shown that two poorly characterized TBONE family members (TBONE1 and TBONE2) are required for biochemical responses triggered by NBPs as well as for bone function. Endogenous nitrogenous phosphonates (NPs), which are chemically related to NBPs and come from our diet and microbiome, potently regulate mineralization in bone-synthesizing osteoblasts in a TBONE1-dependent manner. Lastly, TBONE1 deficient mice have low body mass, deregulated markers of bone remodeling and reduced lifespan. These findings suggest that phosphonates acting through TBONE1 are critical for tissue mineralization

In my lab, we are exploring the TBONE pathway with the following aims: 1) Dissection of the mechanisms of TBONE-phosphonate molecular interactions; 2) Elucidation of the TBONE-phosphonate pathway in the bones and vasculature of mice. The identification of the TBONE family suggests an unexpected new understanding of and path of investigation for some of the most widely used medications, bisphosphonates. Additionally, that naturally occurring phosphonates stimulate mineralization suggests an important new determinant and safer therapeutic approach for numerous aging-associated conditions.

As part of our efforts to identify genes important to Nitrogenous bisphosphonates, we performed genetic screens using human haploid cells with several other commonly prescribed medications including Statins (Atherosclerosis), SSRIs (used in several psychiatric contexts most notably in Depression), Lithium (Bipolar and other Mood disorders). More recently, we have focused our attention on the CRISPRi approach as that method affords greater flexibility in experimental design, e.g., in choice of cell types. We are performing CRISPRi screens on other high-interest molecules and pathways such as those important to mental health and on natural products derived from microbes.

Our initial metabolomics work centers on a Human Metabolite library collated by the Metabolomics Innovation Centre, a Canadian government-funded organization. My lab is using this library to identify regulators of osteoblast function and mineralization in both cell-based and cell-free assays.

While our CRISPRi and metabolite screening will take place in traditional cell culture dishes, there are clear benefits to miniaturization: increased throughput and decreased cost and time. These efforts will focus on microfluidic and other microfabrication approaches. Additionally, we are interested in developing non-invasive methods to measure circulating and tissue metabolites.

• Damon Burrow, Research Technician I (TBONE)
• Chris Chow, Undergraduate (MORPHEOME)
• Christina Gu, Undergraduate (Healthspan/Lifespan)
• Jay Jiang, Undergraduate (MORPHEOME)
• Sandeep Kumar, PhD, Staff Scientist
• Jinmei Li, Lab Manager
• Kevin Li, Undergraduate (Healthspan/Lifespan)
• Melanie Lopez, Undergraduate (CRISPRi screening)
• Ji Woong Park, Graduate Student (MORPHEOME)
• Ryan Young, Undergraduate (CRISPRi screening)