PhD Comprehensive Exam | Melissa Stadt, Mathematical modelling of calcium regulation: Impact of sex, pregnancy, and lactation

MC 6460 

Candidate

Melissa Stadt | Applied Mathematics, University of Waterloo

Title

 Mathematical modelling of calcium regulation: Impact of sex, pregnancy, and lactation

Abstract

Calcium is essential for many biological functions such as skeletal mineralization, muscle contractions, blood coagulation, and cell signaling. While extracellular calcium only makes up a small fraction of total body calcium, it is tightly controlled because too much or too little calcium can cause serious effects on the body. Mathematical modeling has been used to help us better understand the complex physiological mechanisms that regulate calcium levels. However, existing mathematical models have not been explicitly formulated to account for sex differences or the unique physiological states of pregnancy and lactation. In this study we first investigate the impact of known sex differences in calcitriol levels and renal handling of calcium by developing a mathematical model for a female rat. A major difference between female and male bodies, is that female bodies can undergo major changes during pregnancy and lactation to support a rapidly developing fetus and neonate. Indeed, maternal adaptations impact calcium regulation in all mammals. In pregnant rodents, the mother’s body increases calcium intestinal absorption to meet the fetal and expanded plasma volume needs of calcium. In lactating rodents, calcium needs of milk come from bone resorption, intestinal absorption, and enhanced renal reabsorption. Given these observations, the goal of this project is to develop multi-scale whole-body models of calcium homeostasis that represents (1) how sex differences impact calcium homeostasis in female vs. male rats and (2) how a female body adapts to support the excess demands brought on by pregnancy and lactation.

Furthermore, bone remodeling plays a key role in lactational calcium regulation. Lactation is the only state of rapid bone loss in healthy pre-menopausal females. The post-weaning period is also notable because bone loss from lactation recovers rapidly and completely. Bone resorption during lactation is driven by multiple changes such as altered hormone effects and osteolytic osteolysis, where osteocytes act as osteoclasts to resorb the minerals in their surrounded spaces. In this study we seek to develop cell-based population models for a lactating and post-weaning rat to unravel the processes driving these remarkable physiological states. Using our models, we seek to quantify the impacts of osteolytic osteolysis as well as individual hormones in lactational bone resorption and time to post-weaning recovery. This study will be essential in moving towards developing more comprehensive models of calcium regulation in lactating rats.