Overactivity of CB 1 R and iNOS contributes to HPSPF development and progression via multiple critical pathological processes including dysregulation of mitochondrial function and IL-11. Simultaneous inhibition of lung CB 1 R and iNOS by a hybrid inhibitor (MRI-1867) is a rational therapeutic strategy for achieving therapeutic efficacy in HPSPF with attenuating fibrosis, improving pulmonary function and survival.

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Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mouse model generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.of the central nervous system, which include developmental delay, intellectual disability (ID), learning disabilities, autism spectrum disorders, motor and tic disorders, and communication disorders. 2 NDD can be accompanied by non-central nervous system defects, e.g., congenital heart defects (CHD) and facial dysmorphism, in a