Cardiac MechanobiologyLaboratory

Key Research Areas

• Molecular mechanisms of cardiac fibrosis
• Molecular basis of ion channel mechanosensitivity
• Cellular cardiac mechanobiology and novel cellular mechanosensing pathways

Research Overview

There are few environments more mechanical than that of the human heart. It will beat 3.5 billion times during the average person’s lifespan, pumping litres of blood around the body every few minutes. The Cox Lab focusses on understanding the molecular mechanisms of how cells within the heart sense and respond to mechanical forces. These mechanical cues drive physiological processes throughout life from the earliest stages of cardiac development but also contribute to pathological remodelling within the heart in a host of cardiac diseases.

Importantly, mechanical cues contribute to cardiac fibrosis a process central to almost all cardiovascular diseases. Led by Dr Charles Cox, the lab are seeking to understand the mechanical principles and mechanisms that contribute to cardiac fibrosis. These studies will contribute to the development of novel ‘mechano-medicines’, therapeutics that take advantage of the specific mechanical properties of organs or target their mechanosensitivity.

The primary molecules of interest within the Cox Lab are mechanosensitive ion channels. With ongoing projects aimed at understanding the molecular and cellular mechanisms that underlie ion channel mediated mechanotransduction. Ultimately, we seek to exploit our molecular and cellular knowledge to generate ‘mechano-medicines’ that can help individuals and families impacted by cardiovascular disease.

There are three broader projects underway in the Cox Laboratory:

1. Molecular mechanisms of cardiac fibrosis

Fibrosis, a process defined by excessive extracellular matrix (ECM) remodelling, is fundamentally important in the aetiology of many diseases including most cardiac diseases. Fibrotic remodelling within the heart and other organs is a complex interplay of biochemical and biomechanical cues, orchestrated by fibroblasts. This begins as a reparative process to acute stress/injury, aimed at optimal repair and minimum loss of organ efficiency. However, in the heart, the excessive ECM deposition and modification of ECM constituents reduces tissue compliance, increases arrhythmic propensity, and hastens the progression toward heart failure. Thus, understanding how fibroblasts sense and respond to the biochemical and biomechanical cues that ultimately regulate fibrotic remodelling is central to generating widely applicable anti-fibrotic therapies that can preserve or enhance cardiac performance post injury. In collaboration with the labs of Prof Michael Feneley, Prof Boris Martinac and Prof Richard Harvey, utilizing conditional knockout models, we are interrogating the role of mechanosensitive PIEZO channels in cardiac remodelling caused by a number of different pathological cues.

2. Molecular basis of Ion channel mechanosensitivity

Mechanosensitive (MS) ion channels underlie many of the most captivating processes biology has to offer from touch and proprioception to blood pressure sensing. While the primary focus of the Cox Lab are the ubiquitously expressed PIEZO ion channels we also work with other eukaryotic MS channels including members of the OSCA/TMEM63 families and the TRP channel superfamily. This project is aimed at understanding the molecular basis of ion channel mechanosensitivity and deciphering the universal structural and functional principles that govern MS channel gating.

3. Cellular cardiac mechanobiology and novel cellular mechanosensing pathways

MS channels represent only one of the palette of molecular force sensors available to cells. Thus we endeavour to integrate MS channels into the broader mechanosensing landscape with a strong focus on non-myocyte cell types such as cardiac fibroblasts. Recently we identified that PIEZO channels are recruited to integrin mediated adhesions and complex with two transcription factor binding proteins. These facets of PIEZO channel biology represent novel cellular mechanosensing pathways that likely influence the phenotype of cardiac interstitial cells. This project aims to map these pathways and the ultimate consequences on cardiac function I health and disease.

1. Yang S, Miao X, Arnold S, Li B, Ly A, Wang H, Wang M, Guo X, Pathak MM, Zhao W, Cox CD, Shi Z (2022) ‘Membrane curvature governs the distribution of Piezo1 in live cells’. Nature Communications
2. Yao M, Tijore A, Cheng D, Li J, Hariharan A, Martinac B, Nhieu G, Cox CD# & Sheetz MP# (2022) ‘Force and cell-state dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry’. Science Advances (#corresponding authors)
3. Yu Z-Y, Gong H, Kesteven S, Guo Y, Wu J, Li J, Iismaa S, Kaidonis X, Graham R, Cox CD, Feneley M#, Martinac# (2022) ‘Piezo1 is the cardiac mechanosensor that initiates the hypertrophic response to pressure overload’. Nature Cardiovascular Research
4. Zhou Z, Li J, Martinac B & Cox CD (2021) ‘Loss-of-function Piezo1 mutations display altered stability driven by ubiquitination and proteasomal degradation’. Frontiers in Pharmacology
5. Cox CD#, Zhang Y, Zhou Z, Walz T, Martinac B (2021) ‘Cyclodextrins increase membrane tension and are universal activators of mechanosensitive channels’. Proc Natl Acad Sci USA (#corresponding author)
6. Li J, CA Ng, Cheng D, Yao M, Guo Y, Yu ZY, Ramaswamy Y, Ju L, Kuchel PWK, Feneley MP, Fatkin D & Cox CD (2021) ‘Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations’. Communications Biology
7. Zhang Y, Daday C, Gu R-X, Cox CD, Martinac B, de Groot B and Walz T (2021) ‘Visualization of the mechanosensitive channel MscS under membrane tension’. Nature
8. Guo Y, Yu Z-Y, Wu J, Gong H, Kesteven S, Iismaa SE, Chan A, Holman S, Pinto S, Pironet A, Cox CD, Vennekens R, Graham RM, Feneley MP & Martinac B (2021) ‘The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy’. eLife
9. Syeda R, Florendo M, Cox CD, Kefflam J Santos J, Martinac B, Patapoutian A. (2016) ‘Piezo1 channels are inherently mechanosensitive’. Cell Reports
10. Cox CD, Bae C, L Ziegler, Hartley S, Nikolova V, Rohde PR, Ng CA, Sachs F, Gottlieb P, Martinac B (2016) ‘Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 channels are gated by bilayer tension’. Nature Communications

Visit Charles Cox's Google Scholar page for full publications listing.