自噬研究持续升温，美国正关注哪些热点？附经典课题设计思路和基金摘要

“点击↑↑↑，关注临床科研”

前言

我们推送了在美国国立卫生研究院工作的张博士对Autophagy期刊的介绍之后，后台收到了一些信息，询问美国在自噬领域的研究热点

。

为了更好地展现自噬研究概况，我们请美国恒祥咨询公司（Healsan Consulting）做了大数据分析。

检索结果：到目前为止，美国共资助了7,507项与自噬相关的课题，目前在研课题还有958项。

从历年来资助项目数及资助金额可以看到，从2000年开始的2项，一直到2019年达到728项；资助金额也由2000年的56万美元，到2019年的2,456万美元。自噬研究一直在升温。

针对目前在研的958项课题，

研究热点图

热点分类研究

可以看到，转录因子、T细胞、慢病、质控、DNA损伤等是最相关的关键词和研究热点。

转录因子

相关的关键词涉及阿尔茨海默病、动物模型、干细胞、细胞系及IL-1等。

T细胞

与生长因子、动物模型、HIV-1、干细胞、氨基酸等相关。

慢病

则与恶性肿瘤、动物模型、神经系统、细胞系等关联。

质量控制

主要涉及老年性痴呆、干细胞、恶性肿瘤、心力衰竭等领域。

DNA损伤

主要是针细胞周期、干细胞、抗癌、线粒体功能障碍、肿瘤抑制因子等关键词。

承担课题最多的机构

主持课题最多的大学包括宾大、斯坦福大学圣地亚哥分校、密歇根大学安娜堡分校等。

承担课题最多的PI

可以看到，J. David Gladstone学院的Finkbeiner, Steven M主持了7项课题，是在研课题最多的PI；主要研究神经自噬，2020年开始重点关注亨廷顿病的治疗。

我们也可以看到有几位华裔科学家也主持了多项课题，包括August大学的Dong, Zheng，主持了4项课题，主要研究肾损伤与修复，包括缺血性肾损伤和糖尿病肾损伤；西奈山ICAHN医学院的Yue, Zhenyu，主持有三项课题，主要研究神经自噬，尤其是亨廷顿病；堪萨斯大学医学中心的Ding, Wenxing，主持有三项课题，主要从事酒精性肝损伤/胰腺炎损伤中的自噬研究。

借鉴与突破

我们特别对J. David Gladstone学院Finkbeiner, Steven M的神经自噬有兴趣，故做了进一步分析。

其2020年的研究课题摘要如下：

ABSTRACT

The goal of our studies is to identify and validate genes, proteins, and biological pathways that modulate neurodegeneration induced by mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD). This knowledge will provide new insights into the underlying mechanisms of HD and may reveal novel therapeutic targets that are more druggable than mHtt.

While mHtt is the major cause for HD, a number of studies have indicated that genetic modifiers interact with mHtt to affect progression of neurodegeneration in HD. In fact, a substantial genetic contribution to HD is not accounted for solely by the gene that encodes mHtt, or by the few modifiers that have been identified by other research groups.

We hypothesize that rare genetic variants contribute to the disease onset and progression of HD that have been missed by genome-wide association studies (GWAS) or candidate-based approaches.

With this in mind, we conducted whole-genome sequencing (WGS) on multiple HD families and identified candidates in novel genes not previously implicated in HD. They are involved in protein clearance and other cellular pathways that may contribute to neurodegeneration in HD. We provide direct evidence, for the first time, that a subset of these candidates modify neurodegeneration of human striatal-like HD iPSC-derived neurons (HD striatal i-neuron).

In the proposed studies, we will further validate and investigate the mechanisms by which these potential genetic modifiers modulate neurodegeneration and expand our analysis to additional variants and their cellular pathways that contribute to neurodegeneration in HD. Human neuron models recapitulate several key features of HD, and a form of cellular imaging called robotic microscopy (RM) enables high-throughput (HT), high-content, longitudinal single-neuron analysis of these models. The data sets generated by RM reveal different aspects of neurodegeneration, including survival, analyzed by powerful statistical methods, or changes in neurite length, which is a predictor of cellular stress. Our toolbox uses other powerful approaches to assess a candidates' effects on neurodegeneration, such as an optical-pulse labeling (OPL) technology that can measure the rate of clearance of proteins by proteasome activity or Autophagy within single cells. We have an NIH X01 grant that is sequencing 104 additional members of 19 new HD families for which we have extensive medical records and clinical history on. We will extend our WGS analysis to these families and combine the data to identify a more complete set of interacting gene partners and pathways and to help focus our list of current candidates that contribute to HD onset and trajectory. New putative variants will be tested in our human HD i-neuron model to validate them as potential genetic modifiers and to better define cellular pathways involved in modulating onset of HD.

The discovery of novel genetic modifiers of HD will further elucidate the disease mechanisms in HD and identify new directions for developing disease-modifying therapeutics and for stratifying HD populations for more successful clinical trials.

从该研究摘要，大家可以学习到非常精彩的课题设计思路，及如何写基金摘要。

该课题组也已经发表了多篇论文，包括发表在Cell和Nat. Neurosci.的论文。