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Evaluation of the Role of Macrophage Migratory Inhibitory Factor (MIF) in mediating Stem Cell Analgesia in a Model of Orofacial Pain

Award Number: R01DE031352
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Evaluation of the Role of Macrophage Migratory Inhibitory Factor (MIF) in mediating Stem Cell Analgesia in a Model of Orofacial Pain - Abstract/Project Summary The effectiveness and mechanisms of stem cell-induced analgesia in treating dental pain is unknown. We demonstrate that i.v. injections of human Stem Cells of Apical Papilla (hSCAP) reverse apical periodontitis (infection of a tooth; AP)-induced mechanical allodynia. Moreover, hSCAP primed to periapical granulomas (peripheral sites of tooth infection) attenuate capsaicin (CAP)-evoked intracellular Ca2+ accumulation ([Ca2+]I) from trigeminal (TG) neurons and this effect is inhibited by anti-human macrophage migratory inhibitory factor (MIF)-antibody (Ab). Therefore, here, we will test the central hypothesis that apical periodontitis-induced nociceptive behaviors is reversed by hSCAP-derived release of MIF that directly inhibits TG neuronal activity. We propose the following aims to test the central hypothesis in male and female tissues: Specific Aim 1 will test the hypothesis that hSCAP-derived MIF inhibits TG neuronal activities in vitro and in vivo. We will use anti-human MIF-Ab to evaluate the effect of in vivo release of MIF by hSCAP on mechanical allodynia as well as spontaneous nociception using conditioned placed preference (CPP). Next, using CRISPR-Cas9, we will generate a hSCAP cell line with MIF knockout. This cell line will be used to test the hypothesis that in vitro and in vivo hSCAP-derived MIF inhibits TG neurons and AP-induced pain behaviors. Specific Aim 2 will test the hypothesis that neuronal CXCR4 and CD74 receptors mediate MIF-induced inhibition of TG neuronal activity in vitro and in vivo. MIF signals via the CXCR4 and CD74 receptors (21-23) that are expressed on mouse TG neurons (Fig. 11). We will evaluate the role of CXCR4 using AMD3100, a small molecule CXCR4 antagonist using in vitro Ca2+-imaging and in vivo behavioral assays. Next, we conditionally delete CXCR4 from TG sensory neurons to evaluate the function of CXCR4 receptors in vitro and in vivo. Next, will inject mice with AVV-shRNA against CD74 via an intraganglionic route to assess the effect of neuronal CD74 receptor knockdown on in vivo nociceptive behaviors and as well as in vitro Ca2+-imaging. Specific Aim 3 will determine the signaling pathway/s activated by MIF that contribute inhibition of TG neuronal activity. Signaling via CD74/CXCR4 receptor occurs via Gi/o proteins. We demonstrate that 1) pretreatment with pertussis toxin (PTx) completely reverses hSCAP-induced attenuation of [Ca2+]I (Fig. 15); and 2) MIF inhibits voltage gated Ca2+ currents (VGCaC; Fig 16) that is downstream of G activation. Using electrophysiological approaches, we will determine MIF signaling by determining Gi versus G signaling, type of VGCC inhibited, regulation of channels/receptors commonly known to mediate mechanical and spontaneous behaviors and finally study alternative Gi/o-mediated pathways commonly known post-MIF activation. These studies have high medical significance as they define a novel ligand-receptor system for treating infection-induced pain, possibly leading to new non-opioid analgesics. Importantly, the combined use of human hSCAP in rodent models foster mechanistic research and increases translational significance. RELEVANCE: These studies aim at studying new class of non-opioid analgesics for dental pain.


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 = $417,454 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	4	1/14/2026	NON-COMPETING CONTINUATION	$417,454
														Subtotal = $417,454

Issue Date FY: 2025 ( Subtotal = $463,838 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	001	3	1/17/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	002	3	5/5/2025	NON-COMPETING CONTINUATION	$46,384
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	3	1/15/2025	NON-COMPETING CONTINUATION	$417,454
														Subtotal = $463,838

Issue Date FY: 2024 ( Subtotal = $454,561 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	001	2	6/4/2024	NON-COMPETING CONTINUATION	$37,107
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	2	11/29/2023	NON-COMPETING CONTINUATION	$417,454
														Subtotal = $454,561

Issue Date FY: 2023 ( Subtotal = $463,838 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Oral Diseases and Disorders Research	000	1	12/30/2022	NEW	$463,838
														Subtotal = $463,838

Grand Total All Awards = $1,799,691

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Evaluation of the Role of Macrophage Migratory Inhibitory Factor (MIF) in mediating Stem Cell Analgesia in a Model of Orofacial Pain

Award Number: R01DE031352

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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