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Early life bladder inflammatory events in female mice lead to subsequent LUTS in adulthood

Award Number: R01DK135871
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Early life bladder inflammatory events in female mice lead to subsequent LUTS in adulthood - PROJECT SUMMARY Lower Urinary Tract Symptoms (LUTS) are among the most common reasons to see a urologist across the lifespan and are often accompanied by psychological consequences, such as anxiety and depression. Patients with LUTS may have a disrupted bladder–brain dialogue; they may say “I don’t even feel anything until I am wet”. Better therapeutic options can emerge from a better understanding of the fundamental brain circuits and cells that contribute to LUTS and that contribute to bladder–brain communication. A potential LUTS etiology that merits closer study is early life urinary tract infection (UTI). Clinical studies in females (who have UTIs 4x more often than males) show early life UTIs predict later life LUTS. Basic research on UTIs and other bladder insults in adulthood suggest inflammation underlies acute LUTS and psychological consequences. For example, adult systemic injection of cyclophosphamide (CYP) — the most common noninvasive (catheter-free) way to model UTI-linked inflammation — leads to bladder and psychobehavioral dysfunction. However, there is a striking absence of research on the role of early life UTIs in later life LUTS and psychological consequences. Here we show for the first time that female mice experiencing repeated, early life cystitis after CYP have bladder and psychobehavioral dysfunction in adulthood. These data fuel our hypotheses: Early life CYP-induced cystitis induces bladder and brain inflammation, which disrupts bladder-brain dialogue and leads to lifelong LUTS and psychobehavioral consequences; this later life bladder and brain dysfunction can be reversed by manipulation of key brain circuits in adulthood. In Aim 1, we will define early life CYP-induced inflammatory indices in bladder and brain across the lifespan. In Aim 2, we will determine early-life CYP-induced functional changes in bladder and brain across the lifespan, launching off from our pilot data: repeated, early-life CYP-induced cystitis leads to adulthood voiding dysfunction and anxiety-like behavior. We will use pharmacologic tools to address the mechanism and specificity of these functional changes, and test for anxiety- and depression-like phenotypes throughout life. In Aim 3, we will map and manipulate key components of the brain circuits that contribute to bladder-brain dialogue. Using our proven abilities to assess neuron activity in brain regions central to this dialogue (locus coeruleus, Barrington’s nucleus, frontal cortex), we will record the activity of sets of neurons in freely-moving mice before and after voiding events in our early life CYP model. We hypothesize that early life cystitis disrupts the ability of these neuron types to respond to sensation from the bladder and thus discriminate voiding cycle stages. We will then attempt to reverse the early life cystitis-induced bladder and psychobehavioral dysfunction in later life by optogenetically manipulating the activity of relevant neurons in adulthood, as we have already done in adult models. Given the prevalence of LUTS, the basic experiments proposed here have enormous potential to expand our understanding of how neonatal cystitis influences the bladder-brain dialogue throughout the lifespan.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $570,212 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/18/2025	NON-COMPETING CONTINUATION	$570,212
														Subtotal = $570,212

Issue Date FY: 2024 ( Subtotal = $545,825 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/15/2024	NON-COMPETING CONTINUATION	$34,114
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/2/2024	NON-COMPETING CONTINUATION	$511,711
2024	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/18/2024	NEW	$0
														Subtotal = $545,825

Issue Date FY: 2023 ( Subtotal = $610,766 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/26/2023	NEW	$610,766
														Subtotal = $610,766

Grand Total All Awards = $1,726,803

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Early life bladder inflammatory events in female mice lead to subsequent LUTS in adulthood

Award Number: R01DK135871

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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