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MicroRNA as a Novel Therapeutic Target for Pain in Sickle Cell Disease

Award Number: RF1NS143697
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: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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MicroRNA as a Novel Therapeutic Target for Pain in Sickle Cell Disease - Our long-term goal is to develop effective pharmacological interventions that can alleviate sickle cell pain and improve the quality of life for patients with sickle cell disease (SCD). Approximately 100,000 Americans– primarily African or Hispanic background–suffer from SCD, featured with recurrent episodes of acute vaso- occlusion, hemolytic anemia, and progressive organ damage. Patients with SCD endure frequent episodes of acute crisis pain, as well as persistent, intractable chronic pain throughout their lives. Chronic pain in SCD is refractory to current medications and represents a significant unmet medical challenge. There remains a critical and urgent need to identify novel therapeutic targets for effective pain management in SCD. With a growing appreciation for its functional capacity, microRNA (miRNA) is now recognized as one of the major epigenetic regulators that controls target gene expression at the post-transcriptional level. Our group has dedicated significant research effort to investigate the functional role of miRNA in chronic pain conditions, with a focus on let-7 family microRNA (miRNA). As a developmental timing regulator, let-7 miRNA has been implicated in the fetal-to-adult hemoglobin switch– a critical event associated with the onset of sickle cell pain. Meanwhile, results from our preliminary experiments have demonstrated markedly increased expression of neuronal and circulating exosomal let-7 miRNA in mouse models of SCD, as well as patients with SCD. Prior to our study, it was not known whether targeting let-7 miRNA could alleviate chronic pain in SCD. Strikingly, we have since generated preliminary data that spinal let-7 knockdown significantly reversed persistent pain behaviors in a humanized mouse model of SCD. Moreover, we have established robust methodologies to assess different pain types in mice with SCD. Our studies have revealed the presence of evoked hypersensitivity (tactile allodynia, cold and heat hyperalgesia) and, more importantly, ongoing spontaneous pain in multiple mouse models of SCD. Despite being the chief complaint reported by patients with SCD, mechanistic understanding of ongoing spontaneous pain associated with SCD remain largely unexplored. Based on our preliminary findings and the intriguing properties of let-7 miRNA, we will test the hypothesis that let-7 family miRNA can be a novel therapeutic target for chronic pain in SCD. By identifying molecular and epigenetic mechanisms of let-7 miRNA in sickle cell pain, specific targeting of these mechanisms holds great promise of designing effective pain therapies that can benefit patients with SCD. Successful completion of the study will not only characterize the role of let-7 miRNA as a mechanism, biomarker, and therapeutic target for chronic pain in SCD, but also build up a strong scientific framework for future studies that may ultimately lead to additional translational research.


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 = $1,764,145 )
2025	2025	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/30/2025	NEW	$1,764,145
														Subtotal = $1,764,145

Grand Total All Awards = $1,764,145

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MicroRNA as a Novel Therapeutic Target for Pain in Sickle Cell Disease

Award Number: RF1NS143697

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: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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