Regulation of Secretory and Membrane Protein Biogenesis

我们的实验室感兴趣的机制，新生分泌和膜蛋白易位或整合到内质网膜，适当的修改，折叠，并组装之前，随后运输到细胞的各个部分。一个很大程度上未探索的概念是这样的想法，即易位的某些方面可以在疾病的发病机制中被调节或错误调节。在缺乏对所涉及的基本过程的机械理解的情况下，这一概念很难探讨。随着最近对简单分泌蛋白易位的了解，现在的阶段是要问是否更复杂的底物可以在其生物发生的某些方面受到调控。因此，我们实验室的长期目标是揭示分泌和膜蛋白作为细胞中新的调节位点的生物发生，鉴定所涉及的调节机制和因子，并确定这种类型的调节在细胞生物学和疾病发病机制中的作用。 我们正在使用体外生化系统来重建和研究医学相关的分泌和膜蛋白的生物合成的关键步骤。对扰动特别敏感或被确定为改变疾病相关突变体的步骤被进一步解剖。从这些生物化学研究中获得的见解和工具用于开发与所研究底物相关的疾病病理生理学的特定可检验假设。这些假设进行了测试，在体内模型系统，包括培养的细胞和转基因小鼠。目前，实验室正在研究的蛋白质包括朊病毒蛋白和血管紧张素原，它们分别与神经变性疾病和高血压有关。据设想，这些模型底物的见解将揭示一个非常复杂的调节点，对生理学和疾病有直接的影响。

Our laboratory is interested in the mechanisms by which nascent secretory and membrane proteins are translocated across or integrated into the endoplasmic reticulum membrane, appropriately modified, folded, and assembled prior to subsequent transit to various parts of the cell. One largely unexplored concept is the idea that certain aspects of translocation can be regulated, or misregulated in the pathogenesis of disease. This notion has been difficult to explore in the absence of a mechanistic understanding of the basic processes involved. With the recent insights into simple secretory protein translocation, the stage is now set to ask whether more complex substrates can be subject to regulation in some aspect of their biogenesis. Thus, the long term objectives of our laboratory are to reveal the biogenesis of secretory and membrane proteins as a novel site of regulation in the cell, identify the regulatory mechanisms and factors involved, and define roles for this type of regulation in cell biology and disease pathogenesis. We are using an in vitro biochemical system to reconstitute and study key steps in the biogenesis of medically relevant secretory and membrane proteins. Steps that are particularly sensitive to perturbation or are determined to be altered for disease-associated mutants are dissected further. Insights and tools gained from these biochemical studies are used to develop specific testable hypotheses on the pathophysiology of diseases associated with the substrates under study. These hypotheses are tested using in vivo model systems including cultured cells and transgenic mice. At present, proteins under study in the laboratory include the prion protein and angiotensinogen, which are involved in neurodegenerative disease and hypertension, respectively. It is envisioned that the insights from these model substrates will reveal a richly complex point of regulation that has direct implications for physiology and disease.