2016 Research Projects of CCHS Network


Gene Expression Profile of Specific Respiratory Brainstem Neurons Sensitive to CCHS Mutations in Mice

research_miceA small cluster of excitatory brain cells (neurons) serve as an integrative nexus for control of breathing; these neurons express Phox2b, the transcription factor that is mutated in CCHS, and their dysfunction is implicated in the central hypoventilation associated with CCHS. The proposed work uses cutting-edge, single cell sequencing approaches to provide a first comprehensive examination of the genes that are uniquely expressed in these Phox2b-expressing neurons. This work will provide new information regarding the molecular genetics of this vulnerable population of brain cells, and thus new understanding of how those cells perform their specific functions that are critical for breathing and disrupted in CCHS.


Next Generation Sequencing (NGS) Approach to Deepen into PHOX2B Mutations Mediated Pathogenesis
and to Identify Drugs Able to Rescue Cellular and Molecular Defects in CCHS

research_ngsOne of the main obstacles preventing the development of a pharmacological strategy effective in counteracting the damaging effects of PHOX2B mutations in CCHS is the limited knowledge we have gained so far about the patho-physiology of PHOX2B: the genes it regulates, the companion protein factors it interacts with, the time when and the place where its action is indispensable, the pathways it is involved in, the gene networks it gives rise to are poorly known or still lacking information. Therefore, in the present pilot study, 1) genes and pathways involved in PHOX2B mutations mediated pathogenesis will be identified by assessing the gene expression profile of cell lines bearing different PHOX2B mutation; 2) these results will be used, applying proper statistical approaches, to rank genes and pathways resulting to drive the most deleterious effects of PHOX2B mutations in CCHS cell models: the top ones will represent highly desired drug targets; 3) drugs that may have a beneficial effect in CCHS will be predicted starting from above differential gene expression data and taking advantage of available online tools (the Ingenuity Pathway Analysis (IPA), the Connectivity Map (cMap), and the Mode of Action by NeTwoRk Analysis (MANTRA) that do examine the connections among diseases, genes and drugs. Successive stages of this research will be drugs identified as potentially beneficial will be validated in vitro and eventually assessed in clinical trials.


2016 CCHS Research Summary Reports

For Release To Social Media, Network Emails, and Press Release

In 2016 the CCHS Foundation and CCHS Network funded two projects approved for study by the CCHS Research Advisory Board.

“The work by Dr. Isabella Ceccherini and Dr. Doug Bayliss is advancing and they continue to make meaningful progress in the understanding of PHOX2B-mediated cellular dysfunction.”
~Dr. Eddy Yang, M.D., Ph.D, Chair of CCHS Research Advisory Board

Both researchers will report more extensively on their findings at the 2018 CCHS International Research and Family Conference in St. Louis, June 20-23, but we share brief summary reports at this time.

  • The Ceccherini laboratory, with support from CCHS Network, have profiled cells carrying various mutations of the PHOX2B gene, the gene that is responsible for CCHS. They have identified several important cellular pathways that could be novel therapeutic targets. Further work is underway to (1) test the importance of these pathways in CCHS pathogenesis (ranking PHOX2B mutation with deleterious effects) and (2) determine the differential effects of the drug(s) on these pathways.
  • The Bayliss laboratory, with support from CCHS Network, has performed profiling of individual neurons of the retrotrapezoid neurons (RTN), which are responsible for the sensing of CO2 levels in the blood to regulate breathing. RTN neurons are known to be damaged in CCHS. They have identified several novel and interesting RTN gene expression patterns. Based on the results they are now investigating these patterns to gain further insight into CCHS pathophysiology. Doug Bayliss reports, “We expect that this hypotheses generating pilot work will continue to yield deeper understanding of the physiological function of Phox2b and the Phox2b-expressing RTN neurons that are disrupted in CCHS patients.”

The CCHS Network thanks the Ceccherini and Bayliss labs for their continued work on CCHS. Their dedication toward uncovering the particulars of CCHS pathogenesis and regulation of breathing moves us closer to better treatment options for CCHS patients.

The CCHS Foundation and the CCHS Research Advisory Board are both subsidiaries of the CCHS Network. Please visit our website at cchsnetwork.org for more information.