Senescence-Chips for Radiation Biodosimetry

DESCRIPTION provided by applicant Ideal biomarkers of acute and delayed radiation injury after a radiological nuclear terrorist incident are those that arise and are measurable prio to manifestation of tissue injuries typically one to a few days after ionizing radiation IR exposure They should also be measurable in a non invasive or minimally invasive way for example using peripheral blood samples High dose IR induces acute and delayed injuries to both hematopoietic and solid tissues Hematopoietic stem cells HSCs and mesenchymal stem cells MSCs are critical for regenerating and repairing these tissues MSCs differentiate into osteoblasts chondrocytes and adipocytes while HSCs are precursors of various types of blood cells We showed that HSCs and MSCs undergo IR induced senescence a stable post mitotic state after IR In contrast most differentiated blood cells undergo apoptosis after IR and are quickly cleared HSCs and MSCs generally reside in the bone marrow but small numbers can always be detected and isolated from peripheral blood In this SBIR project we propose to use cellular senescence as the biological end point for radiation biodosimetry We will develop integrated microfluidic chips termed andquot Senescence Chipsandquot for rapid and accurate detection of senescent cells particularly IR induced senescent HSCs and MSCs as well as circulating cytokines chemokines due to the senescence associated secretory phenotype SASP from small volumes of human peripheral blood The project builds on our recently published progress in characterizing the IR induced senescence of HSCs and MSCs the SASP as a stable chronic phenotype of senescent cells and the development of a new mouse model p MR C BL mice that allows us to identify track and importantly inducibly kill senescent cell in vivo and at will Our novel microfluidic chips contain multiple functional modules that will capture and enumerate the total and senescent populations of HSCs and MSCs down to single cells and simultaneously detect SASP in peripheral blood The chips will be validated using cell lines mouse models and human clinical samples Senescence chips will enable low cost reproducible highly specific and sensitive multiplex measurements of human peripheral blood for radiation biodosimetry thus serving as a field deployable platform for radiological nuclear medical countermeasures including emergency triage and medical responses PUBLIC HEALTH RELEVANCE Cutting edge technologies enable breakthroughs in biomedicine The proposed microfluidic chips will serve as a field deployable low cost highly specific and sensitive and high throughput platform for minimally invasive radiation biodosimetry and provide new strategies for radiological nuclear medical countermeasures