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Investigation of brain-originating circRNAs as targets in blood-based stroke triage diagnostics

Award Number: R01NS129876
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Investigation of brain-originating circRNAs as targets in blood-based stroke triage diagnostics - PROJECT SUMMARY Stroke is currently the leading cause of permanent disability and fifth leading cause of death in the United States. Early and accurate recognition reduces mortality and morbidity by expediting access to neurocritical care. Unfortunately, recognition of stroke during triage is dependent on symptom-based assessments that are often unreliable, and up to 35% of patients are misdiagnosed at initial clinician contact. Thus, the development of accurate biomarker-based screening tools that could be used to rapidly detect stroke in emergency medicine settings could substantially reduce rates of mistriage, enable earlier access to intervention, and improve patient outcomes. Numerous prior investigations have attempted to use blood measures of various proteins released from damaged neural tissue as an indicator of stroke. Unfortunately, it is now known that many of the proteins targeted in these prior studies exhibit a limited degree of enrichment in brain tissue, curtailing their diagnostic specificity. Furthermore, they typically circulate at too low of levels to enable reliable detection using the immunoassay platforms available for rapid blood testing in emergency medicine settings, blocking their path to clinical use. Circular RNAs (circRNAs) are a family of circularly continuous non-coding transcripts that are resistant to RNase degradation; they accumulate in long-lived cells such as neurons, and recent work has demonstrated that there are variants which are truly found only in the brain. In addition to the potential for improved diagnostic specificity, targeting brain-specific circRNAs released from damaged neural tissue could have significant translational advantages over targeting the proteins studied for blood-based stroke recognition in the past. The amplification methods used to measure nucleic acids are thousands of times more sensitive than the immunoassay techniques used to measure proteins, which could dramatically increase the odds of detection. Furthermore, because these circRNAs would be cell-free, they could be directly assayed in serum without upstream RNA isolation; this could allow for rapid direct detection using qRT-PCR on existing hardware found in clinical labs, or even methods such as loop-mediated isothermal amplification (LAMP) at the point-of-care. Despite these tremendous advantages, brain-originating circRNAs have never been investigated as a potential source of biomarkers for stroke recognition. In the work proposed here, we aim to use digital droplet PCR to evaluate the absolute circulating levels of five brain-specific circRNAs in 500 patients with various cerebrovascular and non-cerebrovascular pathologies who present with stroke-like symptoms at hospital admission, as well as develop a set of clinically viable custom rapid qRT-PCR and LAMP assays targeting said circRNAs and evaluate their sensitivity and specificity for stroke. This novel, innovative, and highly translational project addresses an area of dire clinical need; we fully expect the assays generated as part of this work to establish the immediate technical and molecular foundation for the downstream development of a pair of rapid stroke triage diagnostics: one that could be deployed for stat testing in the clinical laboratory on existing hardware, and another that could be deployed at the point-of-care.


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: 2026 ( Subtotal = $627,857 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/19/2026	NON-COMPETING CONTINUATION	$627,857
														Subtotal = $627,857

Issue Date FY: 2025 ( Subtotal = $596,115 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/15/2025	NON-COMPETING CONTINUATION	$596,115
														Subtotal = $596,115

Issue Date FY: 2024 ( Subtotal = $576,229 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/20/2024	NON-COMPETING CONTINUATION	$534,645
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/25/2024	NON-COMPETING CONTINUATION	$41,584
														Subtotal = $576,229

Issue Date FY: 2023 ( Subtotal = $609,207 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/4/2023	NEW	$0
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/10/2023	NEW	$609,207
														Subtotal = $609,207

Grand Total All Awards = $2,409,408

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Investigation of brain-originating circRNAs as targets in blood-based stroke triage diagnostics

Award Number: R01NS129876

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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