Current Projects

Population-based approaches to investigate endocrine communication

Multicellular organisms have evolved dynamic means of communication between cell types to maintain proper physiologic homeostasis. In mammals, secreted peptides have been described to regulate nearly all aspects of physiology.  The human genome encodes over 3000 proteins which are secreted, of which only ~30% have known or suggestive functions.  Implicating these proteins in their modes of action, target tissue(s) and respective physiologic roles requires expensive and time-consuming experimental investigation.  We developed several approaches that use mapping and correlation structure to statistically rank, and functionally annotate, new modes of tissue-tissue interaction by focusing on secreted proteins.  Specifically, we integrate mouse and human “omics” data to survey natural variation for conserved mechanisms of endocrine communication.  We have further provided in vitro and in vivo evidence for several novel predicted interactions.  These include LCN5, an adipose-derived enhancer of muscle respiration; ITIH5, a fat-expressed suppressor of cardiac starvation response and hypertrophy, and many others.  We aim to 1) employ experimental approaches to understand why these circuits of endocrine communication have been conserved throughout evolution and  2) survey additional population datasets using computational approaches to identify new regulators of cell-cell interaction.

Genetic sex as a driver of myokine signaling 

As the largest organ inside the human body, skeletal muscle is a major regulator of physiologic and metabolic homeostasis. Proteins secreted from skeletal muscle, termed myokines, allow muscle to impact systemic physiology and disease.  Myokines play critical roles in a variety of processes, including metabolic homeostasis, exercise improvements, inflammation, cancer and cognitive functions.  Despite the clear relevance of these factors in mediating a multitude of physiological outcomes, the genetic architecture, regulation and functions of myokines remains inadequately understood.  Given that genetic sex contributes critically to nearly every physiologic outcome, it is essential to consider when relating specific mechanisms to complex genetic and metabolic interactions.  Specifically, many metabolic traits impacted by myokines show striking sex differences arising from hormonal, genetic or gene-by-sex interactions. A focus of the lab is to leverage natural genetic correlation structure of gene expression both within and across tissues to understand how muscle interacts with metabolic tissues. We are working to provide a population genetics framework for inferring muscle signaling to metabolic tissues in humans.  In this light, we found genetic sex and estradiol receptor signaling as critical variables when assaying myokine functions and how changes in cell composition are predicted to impact other metabolic organs.

Current publications can be found here  

                       ____________________________

Systems genetics in the context of Polycystic Ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting 8–12% of reproductive age women, and is characterized by the presence of ovarian cysts, oligo or anovulation and clinical or biochemical hyperandrogenism.

The etiology of PCOS is largely unknown, however genetic and environmental factors such as obesity, endocrine disruption, prenatal and peripubertal life events appear to be major driving forces.  Moreover, several key metabolic abnormalities such as insulin resistance, liver disease, cardiovascular disease and obesity are strongly linked to PCOS.

In our lab the aim is to use a systems genetics approach to interrogate genetic variation and concordant metabolic and reproductive traits by assessing a genetically diverse mouse panel in the context of a PCOS model to reveal new mechanisms associated with this highly prevalent female endocrinopathy.

By means of this approach we also aim to provide a population genetics framework for the assessment of female physiology both in normal physiological and in a PCOS-like setting.

Current publications can be found here