STTR Phase I: Autologous Hematopoietic Stem Cell Production to End Graft-Versus-Host Disease

这个小企业技术转让（STTR）第一阶段项目的更广泛的影响是潜在的消除移植物抗宿主病（GVHD）。移植物抗宿主病是一种毁灭性的疾病，折磨着正在从化疗中恢复的移植受者，他们的骨髓功能和免疫系统受到抑制。GVHD相关疾病导致这些患者过早死亡的比率非常高。该项目的重点是开发一种新的生物计算平台，以生成患者源性干细胞，随后将其重新引入同一癌症患者。这完全绕过了第三方骨髓和血液捐赠，减少并可能消除致命的GVHD，并大大改善结果。使用直接来自同一患者的细胞（例如皮肤细胞）重建血液系统被认为是血液系统再生生物学研究的最高和最具挑战性的目标之一。这将推进生物信息学和细胞治疗研究，并将推进癌症治疗和个性化医疗的最新技术。拟议的项目将使用高保真原型计算工具来生成用于细胞转分化的转录因子配方，通过系统和高通量湿实验室验证来测试这些预测配方，并证明了自体产生持久性HSC的概念证明，所述持久性HSC维持长期的多谱系植入和自我更新，可能使整个血液谱系重演。该项目的范围包括努力调查，识别和采购适当的初始细胞类型;确定细胞类型特异性预测重编程为HSC;优先考虑最有前途的配方并进行适当的病毒转导;创建目标HSC的体外类似物并确定与人类HSC表型的对齐;并对顶级转录因子配方进行重编程实验。数据分析将包括重编程HSC、体外类似物HSC、原代人HSC和先前发表的生产HSC的数据的关键比较。HSC从根本上不同于先前用计算工具靶向的分化细胞类型，因为它们保留了增殖潜力，因此非常难以产生。这个具有挑战性的系统的概念验证不仅将解决GVHD问题，还将进一步证明整个生物计算平台在许多其他生物系统和潜在治疗中的有效性。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

The broader impact of this Small Business Technology Transfer (STTR) Phase I project is the potential elimination of Graft-Versus-Host Disease (GVHD). GVHD is a devastating illness that afflicts transplant recipients who are recovering from chemotherapy and who suffer from suppression of their bone marrow function and immune system. GVHD associated illnesses lead to a very high rate of premature death in these patients. This project focuses on the development of a novel biocomputational platform to generate patient-derived stem cells to be subsequently reintroduced to the same cancer patient. This completely bypasses third-party bone marrow and blood donations, decreasing, and potentially eliminating, lethal GVHD and drastically improving outcomes. The use of cells derived directly from the same patient (e.g. skin cells) to reconstitute the blood system is considered one of the highest and most challenging goals of blood system regenerative biology research. This will advance bioinformatics and cell therapy research and will advance the state-of-the-art in cancer treatment and personalized medicine.The proposed project will use a high-fidelity prototype computational tool to generate transcription factor recipes for cellular transdifferentiation, test those predicted recipes through systematic and high-throughput wetlab validations, and demonstrate proof of concept for the autologous production of persistent HSCs that maintain long-term multilineage engraftment and self-renewal, potentially enabling recapitulation of the entire blood lineage. The project scope includes an effort to survey, identify, and procure appropriate initial cell types; determine cell type-specific predictions for reprogramming into HSCs; prioritize the most promising recipes and carry out appropriate viral transductions; create an in vitro analog of target HSCs and determine alignment with the human HSC phenotype; and perform reprogramming experiments for the top transcription factor recipes. Data analysis will include key comparisons of reprogrammed HSCs, in vitro analog HSCs, primary human HSCs, and data from prior published efforts to produce HSCs. HSCs are fundamentally different from the differentiated cell types previously targeted with the computational tool, as they retain proliferative potential and are therefore very difficult to generate. Proof of concept in this challenging system will not only address GVHD, but also further prove the efficacy of the overall biocomputational platform for use in numerous other biological systems and potential cures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.