ABSTRACT The hematopoietic system is very sensitive to a variety of stresses. Radiation therapy commonly results in not only acute hematopoietic suppression but also long-term bone marrow (BM) injury with increased risk of BM failure or malignancy. Accumulation of damages during aging process is another type of stress on HSCs. Enhancing HSC survival and maintaining their genomic integrity upon stress are crucial for preservation of HSC self-renewal function and for protection against stress-induced BM injury. However, the underlying molecular mechanisms are not well defined. No effective treatment has been developed to prevent or treat stress-induced HSC damages and related pathological consequences. The primary goal of this project is to identify novel pharmaceutical compounds and transcriptional mechanism that target a HSC stress regulatory protein, latexin (Lxn), and to uncover the mechanisms that Lxn suppression results in radiation protection and HSC rejuvenation. We have identified a novel Lxn inhibitor small compound and found that it significantly increases survival by protecting HSCs via a newly identified canonical mechanism of carboxypeptidase A inhibition upon radiation. Lxn deletion also mitigates aging-related functional decline of HSCs. We hypothesize that pharmaceutical and transcriptional suppression of Lxn protects HSCs and blood system from stress (radiation and aging)-induced functional decline via the upregulation of canonical CPA3 pathway. Aim 1 is to determine the molecular mechanisms by which Lxn inactivation protects against radiation-induced BM injury via up-regulation of canonical CPA3 pathway. Aim 2 is to identify the mechanism of action of Lxn lead inhibitor in radiation protection of hematopoietic system. Aim 3 is to define the role of Lxn suppression in rejuvenating old HSCs. Findings will advance our knowledge of novel mechanisms how Lxn regulates stress hematopoiesis. Results will provide a compelling starting point and lay grounds for the novel drug discovery by targeting Lxn, which will benefit patients subject to radiation treatment and old people with dysfunctional HSC and immune aging.

PROJECT NARRATIVE Mitigation and protection of bone marrow cells, particularly hematopoietic (blood forming) stem cells, from radiation and aging-induced acute and permanent injury is critical for the quality of life of cancer patients receiving radiotherapy and for the elderly. This study will investigate pharmaceutic and genetic inhibition of hematopoietic stress regulatory gene, latexin, in radiation protection and stem cell rejuvenation.