Investigation of bladder mucosal microvasculature dysfunction after radiotherapy and its impact on bladder function

Radiotherapy is used to treat almost 50% of all cancers, with both curative and palliative intent. Pelvic malignancies including bladder, prostate and cervical cancers are commonly treated with radiotherapy and around 40% of patents experience radiation-induced bladder toxicity. This is experienced as urinary urgency, frequent urination, radiation cystitis, haematuria (which can be significant), incomplete bladder emptying, nocturia and bladder pain.

The underlying mechanisms of radiation-induced bladder toxicity are not well understood; however, the field is converging on (1) tissue fibrosis and (2) ischaemic damage to the bladder microvasculature.

This project aims to elucidate the underlying pathophysiology of radiation-bladder ischaemia and understand how this leads to bladder dysfunction.

A portfolio of laboratory techniques will be harnessed to understand this significant clinical problem and full training will be given. The project will utilise several advanced imaging methodologies: live-cell Ca2+-imaging, confocal/multiphoton microscopy and electron microscopy. In addition, ultrasound measurement of blood flow, urination assays and molecular techniques e.g. cell culture, qPCR, Western blot will all be used to build a comprehensive understanding of the molecular mechanisms and cellular remodelling driving radiation-induced bladder toxicity.

Radiotherapy is used in the treatment of almost half of all cancers, with both curative and palliative intent. Pelvic malignancies including bladder, prostate and cervical cancers are commonly treated with radiotherapy and around 40% of patents experience radiation-induced bladder toxicity. This is experienced as lower urinary tract symptoms (LUTS), which include urinary urgency, frequent urination, radiation cystitis, haematuria (which can be significant), incomplete bladder emptying, nocturia and bladder pain.

Urinary dysfunction impacts health-related and socioeconomic quality of life and is an under-researched area. At think-tanks, co-led by McCloskey at the International Consultation on Incontinence Research Symposium (ICI-RS 2019), clinicians and scientists concluded that radiation-induced ischemic damage, was a significant cause of bladder dysfunction. This project aims to elucidate the underlying pathophysiology of radiation-bladder ischaemia and understand how this leads to bladder dysfunction.

The project is co-supervised by Professor McCloskey in the Patrick G Johnston Centre for Cancer Research (PGJCCR), an expert on bladder physiology, and Professor Curtis in the Wellcome-Wolfson Institute for Experimental Medicine (WWIEM), an expert in microvascular physiology.

This collaborative, team-science approach means that the student will have the advantage of being embedded within the rich environments of the PGJCCR and WWIEM, learning from complementary seminar series and engaging with scientific and clinical researchers across cancer, radiation biology, microvascular physiology and novel in vivo models. 

The underlying mechanisms of radiation-induced bladder toxicity are not well understood; however, the field is converging on (1) tissue fibrosis and (2) ischaemic damage to the bladder microvasculature.

The bladder has a rich microvasculature in the mucosal layer which supports the metabolic needs of the detrusor smooth muscle and the urothelium. Following radiotherapy, blood vessels and the urothelium become leaky, leading to cystitis and haematuria. Concomitant vascular insufficiency is thought to lead to ischaemic damage to the detrusor and urothelium, leading to LUTS. Our recent Small-Animal Radiation Research Platform (SARRP) in vivo work has shown that after radiation, frequent urination occurs, with smaller volumes per void and interestingly, the amplitude of bladder contractions are significantly smaller (consistent with insufficient bladder emptying and frequency symptoms).

The proposed project will build on this established model which induces the urinary toxicity phenotype. The following specific aims will be addressed:

1. Characterise the effects of radiation on bladder mucosal microvessel physiology and blood flow
2. Investigate the effect of radiation on Ca²⁺-signalling in pre-capillary arteriole vascular smooth muscle cells, endothelial cells, pericytes and post-capillary venules.
3. Elucidate the underlying molecular mechanisms of ischaemic damage.
4. Investigate remodelling of the bladder microvasculature after radiation at the cellular and ultrastructural level.

It is planned that the student will present their data at a national conference in year 2 and an international conference in year 3 and ultimately, publish the work in quality peer-reviewed journals.