Novel Roles of Platelet Autophagy

Autophagic degradation of intracellular substrates is essential for fitness and survival of eukaryotic cells from yeast to man. New roles of autophagy continue to emerge. Due to the importance of autophagy in cellular functions, defects in autophagy are linked to a broad spectrum of human pathologies, including infection, cancer, neurodegeneration, and cardiovascular diseases. Despite the extensive investigation of autophagy in nucleated cells, autophagy in anucleate platelets has just begun to be studied. We previously published on critical roles for autophagy in both healthy brain and in neurodegenerative diseases. We recently reported an exciting and novel discovery: Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. The long term goal of our studies is to unravel the novel roles for platelet autophagy to ultimately develop much needed therapeutics targeting autophagy for ameliorating cardiovascular diseases. Supported by strong preliminary data, our central hypothesis is that autophagic degradation of platelet granules and mitochondria is essential for normal hemostasis and thrombosis. Utilizing a unique collection of platelet/megakaryocyte-specific autophagy-deficient mouse strains and transgenic mice expressing fluorescently-tagged autophagy machinery, as well as a combination techniques including mass spectrometry-based quantitative proteomics, we will focus on two aims: Aim 1 will determine how autophagy induction activates platelets; Aim 2 will utilize the platelet/megakaryocyte-specific autophagy-deficient mouse strains that are uniquely available in our hands to determine how impairments in platelet autophagy lead to defects in hemostasis and thrombosis. Upon completion, the proposed research will provide a new understanding of platelet cell biology and will potentially guide innovative design targeting autophagy for anti-thrombotic therapeutics and bleeding-disorder treatment.