Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint pain and
debilitating inflammatory flares. There are currently no safe and effective treatments that achieve
long-term remission, and therefore, RA patients are twice as likely to become chronic opioid users
than non-RA pain patients. Maladaptive immune cell function is the underlying cause of RA which
leads to joint inflammation and activation of nociceptor sensory neurons that trigger pain.
Nociceptors, in turn, can regulate immune responses in tissues via peripheral vesicle release.
Joints without sensory innervation are protected from arthritis, underscoring the key role of
sensory neurons in controlling both pain and inflammation. Therefore, the neuroimmune axis is
an excellent potential avenue, to treat RA. However, our understanding of the diverse sensory
neurons and immune cells in the joints, how they interact with each other, and how these
interactions change over the course of RA is limited. This proposal is a five-year plan of research,
training, and career development focused on studying the role of neuroimmune interactions in RA
pain and inflammation. In the two-year mentored phase, I will map the receptor-ligand interactions
between sensory neurons and immune cells at a single-cell resolution in healthy and inflamed
joints to identify neuroimmune pathways linked to arthritis, and also determine which neurons
drive pain in response to immune ligands in arthritis. I will accomplish this by utilizing innovative
approaches to construct receptor-ligand cell-cell interactomes, assess pain behavior in mice using
machine learning and inhibit nociceptor activity in a spatially and temporally controlled manner.
This scientific training will complement the career development activities selected to enhance my
skills in scientific communication, leadership, mentorship, and ethics of scientific conduct. The
insights and skills gained during this training will guide my research in the independent phase,
elucidating how nociceptor-immune interactions contribute to the chronicity of RA. This research
will uncover the biological mechanisms of joint inflammation and guide the development of novel
neuroimmune-based therapies. I have assembled a diverse group of highly accomplished
mentors who will ensure that I receive extensive training in pain neurobiology and in the
assessment of sensory neuronal function in mice. My training will be further enhanced by the
unique scientific environment of the Harvard Medical School and Boston Children’s Hospital
research community, which is geared towards unifying my expertise in immunology and sensory
neuroscience and enabling my successful transition into an independent academic position as a
pain researcher.