Understanding and treating genetic urinary tract disease

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Congenital urinary tract diseases are individually rare but are collectively the main cause of end-stage renal disease in children and young adults. Urofacial syndrome (UFS) is one such disease, an autosomal recessive disorder causing lifelong impaired urinary voiding and potentially fatal kidney complications.We discovered HPSE2 or LRIG2 mutations in families with UFS and described Hpse2 and Lrig2 mutant mice with urination defects and abnormal patterns of bladder nerves. In health, HPSE2 and LRIG2 are expressed in nerves supplying the bladder. Thus, UFS bladder disease involves a peripheral neuropathy.The student will join our research team and undertake four experiments, below, that will markedly complement our programme of work that is in part funded by an MRC Project Grant MR/T016809/1 Preclinical gene therapy for genetic urinary bladder disease and a Kidney Research UK Project Grant Paed_RP_005_20190925 The pathophysiology of a congenital bladder disease.1. We are using adeno-associated virus (AAV) vector-mediated HPSE2 or LRIG2 gene transfer administered to baby mice aimed at ameliorating voiding defects in Hpse2 or Lrig2 mutants. We discovered that untreated UFS mice have impaired nitric-oxide medicated relaxation of the bladder outflow, as well as hypercontractility of the bladder body in response to acetylcholine. The student will determine whether gene therapy is associated with improvement in these physiological parameters.2. The student will also determine whether pharmacologically-active drugs can ameliorate the physiological defects ex vivo. This, as well as section 1 (above), will pave the way for better treatments.3. The student will perform histological analyses of kidneys of untreated and AAV-treated UFS mice to determine whether bladder-targeted gene therapy or pharmacological treatments are associated with changes in inflammation in the kidney and lower renal tract.4. The student will explore the possibility of prenatal gene transfer, as assessed by reporter gene expression, into the differentiating renal tract in vitro, using embryonic organ cultures. These 'proof of principle' experiments using AAV and lentivirus vectors will pave the way prenatal treatment protocols.This study will inform the design of gene therapy for people with UFS or other genetic urinary tract diseases, as being undertaken with AAV vector -mediated gene therapy for spinal muscular atrophy.