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Evaluation of Trigeminal Ganglia Sensory Neuronal Population/s Mediating MIF-Induced Anti-Nociception in a Model of Apical Periodontitis.

Award Number: F30DE033587
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Abstract Despite the success of root canal treatments at treating diseases such as apical periodontitis, 1.8 million patients may experience persistent pain six months after treatment. Apical periodontitis is caused by an infection of the dental pulp leading to mechanical allodynia and inflammation. Persistent dental pain increases cost of burden and intake of analgesic drugs. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids provide incomplete pain relief and adverse effects when taken chronically, highlighting the need for a novel treatment that can provide relief to millions of patients experiencing persistent dental pain. The study of stem cells for their analgesic properties has been rapidly growing in hopes of developing a novel class of analgesics. The efficacy of mesenchymal stem cells has been demonstrated in pre-clinical models of neuropathic pain and in patients diagnosed with migraines and osteoarthritis. Preliminary data demonstrates that intravenous injections of human stem cells of the apical papilla (hSCAP) fully reverses hypersensitivity associated with apical periodontitis in mice. RNA sequencing of hSCAP homed to the infected tooth shows a 133-fold increase in the expression of the cytokine Macrophage Migratory Inhibitory Factor (MIF). Additionally, MIF receptors CD74 and CXCR4 colocalize on TRPV1+ neurons in the trigeminal ganglia. Moreover, a local injection of recombinant MIF reverses hypersensitivity associated with apical periodontitis. Lastly, conditioned media from co-cultures of mouse periapical granulomas (the infected tooth) and hSCAP attenuates capsaicin evoked Ca2+ response from trigeminal ganglia neurons and is inhibited with pre-treatment of a MIF antibody. This data supports a novel mechanism for stem cell anti-nociception through the direct effect of stem cells that is possibly mediated by MIF. However, despite primary data suggesting MIF directly inhibits trigeminal ganglia neuronal activity, the neuronal subtypes that MIF-induced anti-nociception are unknown. The pain induced by apical periodontitis is often reported as referred, suggesting the involvement of non-nociceptive fibers due to central sensitization. Understanding which of these subpopulations mediate MIF-induced anti-nociception will allow us to develop targeted treatments for persistent dental pain associated with apical periodontitis. We will test the central hypothesis that MIF-induced inhibition of trigeminal ganglia neuronal activity is mediated by nociceptive and non- nociceptive neurons. To test this hypothesis, we will 1) conduct single cell RT-PCR and immunohistochemistry to determine co-expression of MIF receptors CD74 and CXCR4 with different neuronal markers and 2) use Cre- recombinase to conditionally knockout MIF receptors CD74 and CXCR4 from specific neuronal populations in vivo and evaluate their contributions to MIF anti-nociception in a model of apical periodontitis. These studies will not only provide novel insight into the neuronal populations that mediate MIF-induced anti-nociception but also serve as an excellent training vehicle for my career as a clinician-scientist.


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 = $54,208 )
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	2	11/22/2024	NON-COMPETING CONTINUATION	$54,208
														Subtotal = $54,208

Issue Date FY: 2023 ( Subtotal = $53,494 )
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	9/14/2023	NEW	$53,494
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	001	1	9/14/2023	NEW	$0
														Subtotal = $53,494

Grand Total All Awards = $107,702

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Evaluation of Trigeminal Ganglia Sensory Neuronal Population/s Mediating MIF-Induced Anti-Nociception in a Model of Apical Periodontitis.

Award Number: F30DE033587

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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