Pathologic BIM Suppression & Pharmacologic BH3 Replacement in B-Cell Lymphoma

描述(由申请人提供)：bcl-2家族包括一个基本的蛋白质网络，支配细胞的生存或死亡决定。BIM是BCL-2家族中唯一一种促凋亡的BH3蛋白，是B细胞稳态的主要调节因子，其功能抑制被认为是B细胞淋巴瘤的关键致病因素。这项建议的目的是研究和调节B细胞中这一关键的、非调控的凋亡途径，并应用这些机制的见解来推进一种新的治疗策略，以重新激活治疗难治性淋巴瘤的细胞死亡。我推测，BIM BH3在触发细胞死亡方面的效力反映了其参与多种关键蛋白靶点和死亡途径的能力，并且使用碳氢化合物结合的多肽以药物取代BIM的“死亡结构域”将恢复细胞死亡，从而对B细胞淋巴瘤起到治疗作用。我将应用多学科方法来(1)测试碳氢化合物装订的BIM BH3螺旋在由不同的凋亡阻断机制驱动的B细胞淋巴瘤中重新激活死亡程序的能力，(2)确定BIM SAHB的明确蛋白质靶点以将细胞活性与原位作用机制联系起来，(3)确定药理BIM BH3替代在人和小鼠B细胞淋巴瘤模型中的治疗潜力。通过将化学、淋巴瘤生物学和发育治疗学相互交织在一起，我的目标是对仅BH3蛋白BIM的促凋亡效力产生新的机械学见解，并确定如何利用这个独特的BH3死亡结构域来重新激活由不同的和临床相关的化疗耐药机制驱动的各种B细胞淋巴瘤的细胞死亡。由具有合成化学、免疫学、细胞凋亡生物学和临床血液学/肿瘤学专业知识的国际公认的导师、合作者和顾问组成的多元化团队领导的为期5年的综合培训计划将为LaBelle博士发展成为一名在化学生物学和癌症医学领域具有独特专业知识的独立研究员提供理想的培训环境。

DESCRIPTION (provided by applicant): The BCL-2 family comprises an essential network of proteins that govern the cell's decision to live or die. BIM, a pro-apoptotic BH3-only protein of the BCL-2 family is a master regulator of B-cell homeostasis and its functional suppression is believed to be a key pathogenic factor in B-cell lymphoma. The goal of this proposal is to investigate and modulate this critical, deregulated component of the apoptotic pathway in B-cells and apply the mechanistic insights to advance a novel therapeutic strategy for reactivating cell death in treatment- refractory lymphoma. I hypothesize that the potency of BIM BH3 in triggering cell death reflects its capacity to engage a diversity of key protein targets and death pathways, and that pharmacologic replacement of BIM's "death domain" using a hydrocarbon-stapled peptide will restore cell death for therapeutic benefit in B-cell lymphoma. I will apply a multidisciplinary approach to (1) test the capacity of a hydrocarbon-stapled BIM BH3 helix to reactivate the death program in B-cell lymphomas driven by distinct mechanisms of apoptotic blockade, (2) identify the explicit protein targets of BIM SAHB to link cellular activity to in situ mechanism of action, (3) determine the therapeutic potential of pharmacologic BIM BH3 replacement in mouse models of human and murine B-cell lymphoma. By intertwining chemistry, lymphoma biology, and developmental therapeutics, I aim to generate fresh mechanistic insight into the pro-apoptotic potency of the BH3-only protein BIM and determine how this unique BH3 death domain can be harnessed to reactivate cell death in diverse B-cell lymphomas driven by distinct and clinically-relevant chemoresistance mechanisms. A 5-year comprehensive training program led by a diverse team of internationally-recognized mentors, collaborators, and advisors with expertise in the fields of synthetic chemistry, immunology, apoptosis biology, and clinical hematology/oncology will provide an ideal training environment for Dr. LaBelle's development into an independent investigator with unique expertise at the interface of chemical biology and cancer medicine.