2018-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/697911摘要：骨髓分化系統為脊椎動物造血系統之重要分支，本實驗室過去研究指出，於人類血 球幹細胞、斑馬魚及BALB/c小鼠中，水解磷酸脂(lysophosphatidic acid, LPA) 藉 由活化其第二及第三型受器對於骨髓分化系統中紅血球的分化有相互結抗的調控現 象，但此兩型受器對於骨髓系統分化的調控機制尚不清楚。因此在此計畫中，我們 針對水解磷酸脂受器在骨髓分化系統中的前驅細胞及紅血球成熟過程中的調控機制 做進一步的探討。初步實驗結果顯示，此兩型受器表現於骨髓分化系統的不同時期 ，第二型受器作用於上游前驅細胞-共同血球前驅細胞(Common myeloid progenitor, CMP)，並抑制其分化能力;而第三型受器則表現於較晚期的前驅細胞- 巨核細胞/紅血球前驅細胞(Megakaryocyte-erythroid progenitor, MEP)，促進其分 化能力。此外，此兩型受器在骨髓系統中的表現趨勢，與已知的GATA轉錄因子族 群的變化呈現一致的模式。 延續上述的初步研究結果，本計畫的第一部分預計利用小鼠模式，以藥物活化受器 來研究此兩型受器對於骨髓血球系統中血球分化的調控機制;於計畫的第二部分 ，我們期望釐清GATA轉錄因子族群與此兩型受器在CMP分化至MEP過程中的交 互關聯性;於計畫的第三部分，基於第三型受器增效劑增加紅血球分化的研究成果 ，我們預計以本實驗室所建立的篩選系統，使用細胞及動物模式篩選出更具專一性 且更穩定的第三型受器增效劑，此項研究成果可望應用於貧血疾病的治療中。<br> Abstract: Myeloid cells differentiation is an important process to maintain blood component of vertebrates. Our previous studies demonstrated that activation of LPA2 and LPA3 oppositely regulate erythrocyte differentiation. This antagonizing effect is conserved among human hematopoietic stem cell, zebrafish embryo, and BALB/c mice. However, the detail mechanism for LPA2 and LPA3 control myeloid differentiation remains elusive. In this proposal, we attempted to clarify the roles of LPA receptors on different stages of myeloid progenitor and erythrocyte maturation. Our preliminary data demonstrated that LPA2 mainly expresses in common myeloid progenitor (CMP) and activation of LPA2 reduces numbers of colony forming units of CMP. In contrast, expression level of LPA3 increased in megakaryocyte-erythroid progenitors (MEP) and activation of LPA3 enhances numbers of colony forming units of MEP. The observed expression pattern switch of LPA2 and LPA3 during myeloid progenitor differentiation is consistent with the well-known “GATA factors switch”. Therefore, the first aim of this study is to clarify the effects of LPA2 and LPA3 during fate specification of myeloid differentiation. Secondly, we will attempt to clarify the relationship between LPA receptors and GATA factors during myeloid differentiation. Finally, we attempt to identify specific and potent LPA3 agonists from compound library using the efficient screening system developed in our laboratory as potential therapeutics for anemia.