Effects of Radiation on Brain Microvasculature and Cognition

描述(申请人提供)：全脑照射(WBI)导致大约20%-50%的脑肿瘤患者在治疗后长期存活的进展性痴呆。目前，还没有预防辐射引起的脑损伤的战略， 没有其他治疗方法可以逆转这些影响。我们的总体目标是开发治疗干预措施，以改善辐射导致的认知障碍的影响。我们的研究是独一无二的，因为我们使用临床相关的分次剂量的WBI，使我们能够得出与WBI反应时发生的认知功能障碍的病因有关的结论。在我们的第一个资金周期中，我们发现辐射诱导的细胞衰老是导致血管和认知功能障碍的潜在机制，骨髓移植可以逆转辐射诱导的认知损伤。我们推测，骨髓移植可以改善脑血管微环境，减少细胞衰老的影响，并允许调节细胞增殖。我们的结果与之前调查辐射对细胞衰老影响的研究结果一致，但我们在将这些发现纳入放射治疗后发生的脑血管和认知功能障碍的病因方面取得了重要进展。这些结果导致了我们目前的假设，即分级的WBI诱导了一种改变大脑微环境的衰老表型。我们的工作是新颖的，因为我们将是第一个证明辐射诱导的细胞衰老是辐射对大脑作用的统一概念。这项工作可能会导致识别能够恢复认知功能的干预的靶向机制。我们将通过为下列特定目的提出的实验来验证这一假说：1)确定衰老和获得衰老相关分泌表型(SASP)是否有助于脑微血管生成反应受损；2)确定全脑辐射是否损害脑血管自我调节反应，损害血流和/或破坏血脑屏障功能；3)确定骨髓移植后血管密度增加和学习记忆恢复的机制。我们之前关于辐射诱导内皮细胞衰老的研究，以及骨髓移植对WBI后恢复血管增殖和认知功能的影响，为我们的应用提供了关键支持。

DESCRIPTION (provided by applicant): Whole brain irradiation (WBI) leads to progressive dementia in approximately 20-50% of brain tumor patients who survive long-term after treatment. At the present time, no strategies exist to prevent radiation- induced brain injury, and no additional treatments can reverse these effects. Our overall goal is to develop therapeutic interventions that ameliorate the effects of radiation-induced cognitive impairment. Our research studies are unique since we use clinically relevant, fractionated doses of WBI allowing us to make conclusions related to the etiology of cognitive dysfunction that occurs in response to WBI. During our first funding cycle, we found that radiation-induced cellular senescence is a potential mechanism that contributes to vascular and cognitive dysfunction and that bone marrow transplants can reverse radiation-induced cognitive impairment. We postulated that bone marrow transplants modify the cerebrovascular microenvironment, reducing the impact of cellular senescence and permit regulated cell proliferation. Our results are consistent with the results of previous studies investigating the effects of radiation on cellular senescence, but we have made important strides in incorporating these findings into the etiology of both cerebrovascular and cognitive dysfunction that occur after radiation therapy. These results have led to our current hypothesis that fractionated WBI induces a senescent phenotype that alters the cerebral microenvironment. Our work is novel in that we will be the first to demonstrate that radiation-induced cellular senescence is a unifying concept for the actions of radiation on the brain. This work will likely lead to the identification of target mechanisms for interventions thos are capable of restoring cognitive function. We will examine this hypothesis by the experiments proposed for the following specific aims: 1) Determine whether senescence and acquisition of a senescence-associated secretory phenotype (SASP) contribute to the impaired angiogenic response of cerebral microvessels; 2) Determine whether whole brain radiation impairs cerebrovascular autoregulatory responses, impairs blood flow and/or disrupts blood-brain barrier function; 3) Identify the mechanisms for the increase in vascular density and recovery of learning and memory after bone marrow transplantation. Our previous studies of radiation-induced cellular senescence in endothelial cells and the effects of bone marrow transplants that restore both vascular proliferation and cognitive function after WBI provide key support for our application.