Zhu Lab Projects

The emergence of gap junctions is a hallmark in the evolution of life from single-cell to multicellular organisms. For the first time, they enabled true social interactions between cells by allowing the exchange of ions and small molecules, based on which more specialized organs and systems could emerge.

Connexins are the major building blocks for gap junctions, with Connexin43 as the most widely expressed connexin isoform in many organs. Research in the past several decades has established the importance of Cx43 in many physiological processes, and our recent data indicates a vital role of Cx43 in cold-induced adipose tissue beiging. Current projects in the lab focus on the gap junction-dependent functions of Cx43 in adipose tissue metabolism in response to cold, β3-adrenergic receptor agonists, or other hormonal treatments that target the adipose tissue. Based on our research, dual-functional biologics that engage adipocyte metabolism and gap junction activity are in development to improve the efficacy of the starting signaling molecule.

Surprisingly, connexins are relatively new in evolution. The primordial gap junction was made of innexin proteins. Due to a lack of sequence similarities, theories have suggested that innexin and connexin proteins are a convergent solution to the problem of intercellular communication (2). Hence, the question is where connexins came from and whether connexins had other functions in the cell before being recruited to carry out the gap junction function. Surprisingly, connexin proteins, especially Connexin43, can be alternatively translated and targeted to a subcellular region other than the plasma membrane, gaining many gap junction-independent functions. Currently, we are investigating an array of gap junction-independent functions of Cx43 in the adipose tissue. 

This project sprouted out of our interest in the role of adipose tissue in the aesthetic improvement of skin conditions. HA is a linear polysaccharide that is universally made by cells. Together with other matrix components, HA constitutes the extracellular environment, which is vital for cells. Cross-linked HA is widely used for cosmetic dermal fillers, and many other forms of HA are also being developed as cosmetic carriers.

HA synthesis and degradation is very dynamic at the cellular level. It is governed by three known synthases and six degrading enzymes. Most synthesized HA is degraded locally. The rest of HA can be enriched in the lymphatic system and eventually mixed with the blood and cleared by the liver or excreted by the kidneys.

HA plays important roles during the processes of inflammation, wound repair, and skin healing as well as in disease progression, i.e., cancer and nonalcoholic steatohepatitis (NASH). Historically, the study of HA is limited by the purity of its commercial preparation and the lack of animal models in which HA levels can be temporally and spatially modified. We leveraged a Tet-inducible overexpression system and achieved gain-of-function and loss-of-function of the HA content in specific tissues via overexpression of a synthase or degrading enzyme. Leveraging these animal models, we are currently investigating the hepatic clearance of HA and how its accumulation modulates metabolism and the development of liver fibrosis.

Adipose tissue represents a promising target for addressing obesity and metabolic disorders. However, the considerable challenges posed by the large size and limited vascularization of adipocytes, particularly in obese individuals, hinder the effectiveness of pharmacological agents. Through animal models, we successfully demonstrated a proof-of-concept approach that capitalizes on adipocyte Connexin43 gap junctions to augment the impact of molecules and proteins targeting adipose tissue. The integration of the Connexin43 gap junction activator danegaptide markedly improved the effectiveness of FGF21 in promoting weight loss. Building on these insights, our current focus involves engineering FGF21 to selectively target adipose tissue and developing a fusion peptide possessing dual functionalities of FGF21 and danegaptide.

Cell surface proteomics is a thorough examination of proteins located on the outer membrane of cells. The cell surface is a dynamic and complex interface that plays a crucial role in physiology and pathology. A cell's surface also contains handles that allow cell-specific targeting and delivery of biologics. In the context of our FGF21 engineering endeavors, we decided to walk back to understand the compositional difference of cell surface proteome in different cell types for the first time in vivo so that we can unbiasedly design the most potent strategy for cell-specific delivery. 

These projects are currently supported by ARS/CRIS(3092-51000-061), NIH R01DK136619, and NIH R01DK136532.