Cell Polarity in Self-renewal and Differentiation of Stem/Progenitor Cells

描述(申请人提供)：自我更新和分化是所有干细胞/祖细胞的基本特征。在哺乳动物发育过程中，干细胞/祖细胞使用细胞极性机制进行不对称分裂，以更新自己，并产生停止增殖和分化的子代。类似的机制也被用于成体干细胞的自我更新和分化。干细胞不对称分裂的失败可能导致无法退出细胞周期，扰乱正常的大脑发育和癌症。或者，干细胞自我更新失败会导致干细胞枯竭、组织再生能力下降和过早衰老。哺乳动物干细胞/祖细胞的细胞极性和不对称分裂的分子机制以及它们在衰老和癌症中的作用仍然知之甚少。这项建议集中在细胞极性蛋白，致命的巨型幼虫1和2(Lgl1和Lgl2)，这两个蛋白代表果蝇肿瘤抑制蛋白LGL的哺乳动物同源物。我们有证据表明，在神经发生的早期，Lgl1对于调节神经前体细胞的不对称分裂是必需的，而Lgl1的缺失会导致无法退出细胞周期的前体细胞的异常聚集。Lgl1-/-小鼠的新生死亡使我们无法分析Lgls在成年动物中潜在的肿瘤抑制作用以及它们在成年干细胞自我更新中的作用。在这个方案中，我们将使用各种条件基因敲除和生化方法来研究整个LGL基因家族在体内的潜在作用和意义，以及LGL蛋白在调节干/祖细胞自我更新和分化中的作用的分子机制。这些研究将有助于扩大我们对哺乳动物干细胞/祖细胞自我更新和分化机制的认识。这些信息将有助于未来开发高效的再生、抗衰老和抗癌疗法。 公共卫生相关性：该提案中描述的研究将有助于理解干细胞在成年哺乳动物有机体中是如何维持的，以及干细胞的异常是否与癌症有关。在这项研究中获得的知识将有助于开发治疗组织损伤、退行性疾病和癌症的新疗法。

DESCRIPTION (provided by applicant): Self-renewal and differentiation are fundamental characteristics of all stem/progenitor cells. During mammalian development stem/progenitor cells use cell polarity mechanisms to divide asymmetrically to renew themselves and generate daughters that stop proliferation and differentiate. Similar mechanisms are used for self-renewal and differentiation of adult stem cells. Failure of asymmetric cell divisions in stem cells may result in inability to withdraw from cell cycle, perturbations of normal brain development and cancer. Alternatively, failure of stem cell self-renewal can cause depletion of stem cells, decline in tissue regenerative potential and premature aging. The molecular mechanisms governing cell polarity and asymmetric cell divisions of mammalian stem/progenitor cells and their role in aging and cancer are still poorly understood. This proposal focuses on cell polarity proteins, Lethal giant larvae 1 and 2 (Lgl1 and Lgl2), which represent the mammalian orthologs of Drosophila neoplastic tumor-suppressor protein Lgl. We have evidence that Lgl1 is necessary for regulation of asymmetric cell division of neural progenitor cells during early neurogenesis and loss of Lgl1 results in abnormal accumulation of progenitors that fail to withdraw from the cell cycle. Neonatal death of Lgl1-/- mice precluded us from the analysis of potential tumor- suppressor role of Lgls in adult animals and their role in self-renewal of adult stem cells. In this proposal we will use a variety of conditional gene knockout and biochemical approaches to investigate the potential in vivo role and significance of the entire Lgl gene family and molecular mechanisms responsible for function of Lgl proteins in regulation of stem/progenitor cell self-renewal and differentiation. These studies will help to extend our knowledge of the mechanisms of self-renewal and differentiation of mammalian stem/progenitor cells. This information will be useful for future development of efficient regenerative, anti-aging and anti-cancer therapies. PUBLIC HEALTH RELEVANCE: Studies described in this proposal will help to understand how stem cells are maintained in the adult mammalian organism and whether abnormalities with stem cells are responsible for cancer. Knowledge obtained during this study will help to develop new therapies for treatment of tissue injury, degenerative diseases and cancer.