Biology subjects

Puttapaka, S. N.

Publications and source records attributed to Puttapaka, S. N..

3 recordsLinked to original sources

bioRxiv2026

Proteome wide serology reveals immune defined subtypes of gastrointestinal disease in systemic sclerosis

BackgroundGastrointestinal (GI) involvement in systemic sclerosis (SSc) affects up to 90% of patients and is a major driver of morbidity and mortality. Despite its clinical importance, GI disease in SSc is highly heterogeneous, with upper and lower GI manifestations representing distinct phenotypic extremes whose underlying immunologic basis remains poorly defined. MethodsWe performed unbiased, proteome-wide autoantibody profiling using a human protein microarray comprising >21,000 full-length proteins (>80% of the human proteome). Sera from patients with SSc and isolated upper GI dysmotility (n=23), isolated lower GI dysmotility (n=17), and non-SSc controls (n=20) were analyzed. Enriched autoantibodies were identified using Fishers exact test, and unsupervised clustering was applied to define serology-based patient subsets and relate immune signatures to clinical phenotypes. ResultsDistinct autoantibody profiles differentiated patients with upper versus lower GI disease. Upper GI-predominant SSc was characterized by enrichment of previously unreported autoantibodies, including those targeting TiSSc1/2 (newly identified proteins encoded within the MIRLET7BHG locus), FAM9C, SPATA20, FAM110D, EMILIN1, CARD14, SMN1, KCTD7, and PHYHD1, whereas lower GI disease was associated with antibodies against HAO2, KLHL7, SUFU, APPL1, BNIP2, UCHL3, ZNF385A, LIMD1, MAGEA9, and PPP2R3C. Serology-driven clustering identified four reproducible subgroups with distinct patterns of GI, pulmonary, vascular, and autonomic involvement, defining clinically meaningful disease phenotypes that extend beyond traditional anatomic classification. ConclusionsProteome-scale serological profiling reveals previously unrecognized autoimmune signatures underlying GI heterogeneity in SSc. These findings support a shift from anatomy-based to serology-defined classification of SSc GI disease and provide a foundation for biomarker development, patient stratification, and precision medicine approaches in this population.

immunology↗

bioRxiv2026

Enteric neurons modulate colorectal cancer cell cycle through a PCSK1 - Methionine-Enkephalin Axis

Background and AimsThe tumor microenvironment in colorectal cancer (CRC) is richly innervated, yet the contribution of the enteric nervous system (ENS) to CRC biology remains poorly defined. ENS neurons express proenkephalin (PENK), which can be processed by proprotein convertase 1/3 (PCSK1) to generate Methionine-enkephalin (M-ENK), a bioactive peptide with growth-regulatory potential. We hypothesized that an ENS-derived PCSK1-M-ENK axis restrains CRC proliferation through opioid growth factor receptor (OGFr) signaling and is modulated by stress-associated glucocorticoid receptor (GR) signaling and GLP1 receptor (GLP1R) activity. MethodsPublicly available human CRC single-cell RNA-sequencing datasets were analyzed for OGFr expression. PCSK1 and M-ENK expression in murine ENS and tumor-associated tissue was assessed by immunofluorescence. Functional studies were performed using murine CRC organoids, and primary murine ENS neurons in mono- and co-culture. CRC proliferation was quantified by EdU incorporation following treatment with recombinant M-ENK, recombinant PCSK1, OGFr synthetic ligand naloxone, or PCSK1 inhibitors. Effects of dexamethasone and liraglutide on PCSK1 expression in ENS-containing murine tissue were evaluated. ResultsOGFr was enriched in CRC cells and positively associated with KRAS gene expression. A subset of adult murine colonic myenteric neurons expressed PCSK1 and M-ENK. M-ENK dose-dependently suppressed proliferation of CRC organoid cells. ENS neurons also suppressed CRC proliferation in a PCSK1-dependent manner. Dexamethasone reduced, whereas liraglutide increased, PCSK1 expression. ConclusionsThese findings define a previously unrecognized ENS-derived neuro-oncologic pathway that is associated with reduced CRC cell proliferation and identify the GR/GLP1R-PCSK1-M-ENK axis as a potentially actionable therapeutic node. SummaryThis study identifies a neuronal PCSK1 - M-ENK pathway in the ENS that directly suppresses colorectal cancer growth through local OGFr activation, revealing a previously unrecognized neuropeptidergic mechanism of tumor control within the intestinal microenvironment.

cancer biology↗

bioRxiv2026

Loss of enteric BDNF TrkB signaling and VIPergic dysfunction underlie gastrointestinal dysmotility in a Mecp2-null mouse model of Rett syndrome

Gastrointestinal (GI) dysmotility is a highly prevalent and clinically significant feature of Rett syndrome (RTT), yet its underlying mechanisms remain poorly defined. Here, we investigated these mechanisms of GI dysmotility in a Mecp2-null mouse model of RTT. First, we observed that MeCP2 was expressed in murine myenteric ganglia, including in enteric neurons and that Mecp2-null males developed maturation-associated functional regression in their GI motility. In dysmotile mice, longitudinal muscle-myenteric plexus tissue showed marked reductions in enteric Bdnf isoforms IV, VI, and II, whereas expression of the BDNF receptor isoforms TrkB.FL and TrkB.T1 was not significantly altered, consistent with reduced enteric BDNF-TrkB signaling. Despite impaired GI motility, Mecp2-null mice showed no significant changes in total enteric neuronal density, nitrergic neuronal abundance, or expression of Nos1, Chat, and Uchl1. In contrast, Vip expression was significantly reduced, while expression of VIP receptor genes: Vipr1 and Vipr2 was increased, indicating disrupted VIPergic signaling. Integration with publicly available enteric single-cell/nucleus datasets and targeted qRT-PCR further suggested altered inhibitory neuronal subtype composition, with reduced Vip+ Cartpt+ signatures and increased Nfia expression, suggesting that MeCP2 loss differentially affects distinct inhibitory neuronal subpopulations. Finally, conditional loss of TrkB.FL in neural crest-derived cells reduced Vip expression without recapitulating the full Mecp2-null VIPergic phenotype, indicating that impaired BDNF-TrkB signaling contributes to, but does not completely explain, the GI dysmotility in this model of RTT. Together, these findings identify enteric BDNF-TrkB and VIPergic dysfunction as key mechanisms underlying GI dysmotility in RTT.

neuroscience↗