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Principal Investigator: YI-FEN LEE
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2024
Award: $449,295
Funding agency: National Cancer Institute
We propose to study extracellular vesicles (EVs) as novel mediators of the pathogenesis of radiation cystitis
(RC), which affects approximately 15% of prostate cancer (PCa) patients treated with radiotherapy (RT).
Bladder radiotoxicity impacts the lives of PCa survivors, most notably older patients, and there are no
predictive markers associated with its incidence, nor are there durable molecular therapies capable of
preventing RC. There is an urgent need for the development of effective medical countermeasures against RC
and the identification of molecular diagnostics to aid in mitigating this debilitating treatment-related
complication. EVs are lipid-bound nanoparticles that mediate intercellular communication by delivering cargo
molecules to neighboring or distant cells. Studies have shown that RT induces EV release and alters the
composition of these EVs. However, most research to date has been conducted in cell lines, with limited
preclinical studies and no human research. Using preserved samples collected from a genome-wide
association study (GWAS), we reported for the first time a link between urinary EV (uEV) levels and the future
onset of hematuria, providing a promising biomarker that may enable more timely treatment of at-risk patients
to mitigate the development of late bladder toxicities. The prognostic utility of EVs in serum was less robust.
This is further supported by an animal study showing a correlation of uEV particle counts with RT-induced
bladder toxicity. Critically, post-RT uEVs derived from PCa patients who developed late hematuria induced
substantial oxidative stress in normal bladder recipient cells, further supporting a functional link between EVs
and radiotoxicity. Proteomic analyses of 12 uEV samples revealed that those EV cargo proteins were
profoundly altered by RT. Notably, we identified 60 RT-toxicity signature uEV proteins including many with
functions associated with innate immunity and neutrophil activity, highlighting potential mechanism(s) of action.
Based on these studies, we hypothesize that RT induces the release of EVs and alters their composition, and
the resultant RT-EVs carry immunologically active biomolecules, thereby inducing additional cellular damage.
The kinetics of RT-EV release and RT-EV cargo molecules can serve as predictive biomarkers for RT-induced
toxicity that will allow for early intervention to mitigate RT toxicity. We propose three Specific Aims. Aim 1: To
define the roles of radiation-induced extracellular vesicles in mediating RT-induced bladder damage in vitro
and in vivo. Aim 2: Characterization of RT-EV cargo molecules and their roles in mediating radiotoxicity. Aim
3: To establish body fluid-derived EV-based predictive biomarkers for RT-induced toxicity. Accomplishing the
proposed studies will define the functional roles of RT-EVs as mediators of RT toxicity. RT-induced EV release
kinetics and alterations in EV cargos will represent sensitive, noninvasive urine/blood-based EV biomarkers
that can predict clinically relevant RT outcomes before the onset of late toxicities.
Terms: <ACE Inhibitors><Activities of Daily Living><Activities of everyday life><Acute Radiation Syndrome><Affect><Amendment><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Animals><Assay><Attention><Automobile Driving><Bioassay><Biogenesis><Biologic Models><Biological Assay><Biological Markers><Biological Models><Bladder><Bladder Injury><Bladder Urinary System><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood Serum><Body Fluids><Cancer Patient><Cancer Survivor><Cell Body><Cell Line><Cell to Cell Communication and Signaling><Cell-Cell Signaling><CellLine><Cells><Cellular Stress><Cellular Stress Response><Cellular injury><Communication><Complication><DNA Damage><DNA Injury><Development><Dimensions><Distant><Early Diagnosis><Early Intervention><Early-Stage Clinical Trials><Enrollment><Future><GWA study><GWAS><Genes><Hematuria><Human><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><In Vitro><Incidence><Innate Immunity><Investigation><Kinetics><Kininase II Antagonists><Kininase II Inhibitors><Link><Lipid Binding><Lisinopril><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Marrow Neutrophil><Mediating><Mediator><Membrane><Mice><Mice Mammals><Model System><Modern Man><Molecular><Murine><Mus><Native Immunity><Natural Immunity><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Specific Immunity><Nonspecific Immunity><Observation research><Observation study><Observational Study><Observational research><Origin of Life><Oxidative Stress><Pathogenesis><Pathway interactions><Patients><Phase 1 Clinical Trials><Phase I Clinical Trials><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Prevention><Prinivil><Process><Production><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate malignancy><Prostatic Cancer><Proteins><Proteomics><RNA Seq><RNA sequencing><RNAseq><Radiation><Radiation Protection><Radiation Toxicity><Radiation therapy><Radioprotection><Radioprotective><Radiotherapeutics><Radiotherapy><Radiotoxicity><Reporting><Research><Risk><Role><Sampling><Secretory Granules><Secretory Vesicles><Serum><Small RNA><Strains Cell Lines><Symptoms><Time><Toxic effect><Toxicities><Treatment-related toxicity><Urine><Vesicle><Zestril><bio-markers><biologic marker><biomarker><cancer microenvironment><cell damage><cell injury><cell stress><cellular damage><clinical investigation><clinical predictors><clinical relevance><clinically relevant><cultured cell line><cytokine><daily living function><daily living functionality><damage to cells><developmental><driving><early detection><elderly patient><enroll><extracellular vesicles><functional ability><functional capacity><gain of function><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><in vivo><injury to cells><intercellular communication><lipid bound><loss of function><medical countermeasure><membrane structure><molecular diagnostics><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutrophil><novel><older patient><particle><pathway><phase I protocol><pre-clinical><pre-clinical study><preclinical><preclinical study><predictive biomarkers><predictive marker><predictive molecular biomarker><preservation><prevent><preventing><prognostic ability><prognostic power><prognostic utility><prognostic value><prospective><prostate cancer survivors><prostate cancer treatment><prostate survivors><radiation cystitis><radiation poisoning><radiation treatment><radiation-induced cystitis><radio-protection><radio-protective><radioprotected><rapid detection><social role><therapeutic outcome><therapeutic target><therapeutic toxicity><therapy associated toxicity><therapy outcome><therapy related toxicity><therapy toxicity><trafficking><transcriptome sequencing><transcriptomic sequencing><treatment toxicity><treatment with radiation><treatment-associated toxicity><tumor microenvironment><urinary><urinary bladder><vesicle release><vesicular release><whole genome association analysis><whole genome association studies><whole genome association study>