Rescuing radiation-induced cognitive deficits through cranial transplantation of

描述(由申请人提供)： 许多临床研究已经确定了癌症治疗对认知的衰弱副作用，以及这些认知障碍对生活质量的主要影响。对于那些患有原发和转移性脑肿瘤的患者，放射治疗仍然是阻止疾病进展的唯一可行的选择。在美国，每年约有20万名患者接受全脑或部分脑照射，其中一半患者的存活时间超过6个月。到目前为止，仍然没有令人满意的长期治疗方法来减少放射性脑损伤的进行性不良后遗症。儿童病例尤其令人担忧，因为接受头颅放射治疗的儿童智商每年可能会下降3个点，而且往往会在癌症后长寿。即使是引起轻微形态损伤的低剂量颅脑照射也会导致不同程度的认知功能障碍，表现为学习、记忆、注意力、注意力和执行功能的损害。因此，除生存外，癌症临床治疗导致的认知障碍很可能是评估治疗结果和长期生活质量的最关键标准。最近的治疗进展意味着癌症患者的生存时间更长，使长期功能和生活质量成为主要优先事项。上述情况突出表明，迫切需要制定有效的长期战略，以防止认知能力下降。本提案的重点是开发一种创新的干细胞移植战略。在我们之前的研究中，我们发现移植的人胚胎(HESC)和神经干细胞(HNSC)可以拯救辐射诱导的大鼠认知损伤，这为干细胞策略可以有效地改善辐射诱导的正常脑组织损伤提供了第一个证据。基于这些重大而新颖的发现，我们提出了一系列全面的研究，以探讨hNSCs海马区移植恢复颅脑照射大鼠认知能力的翻译潜力和机制基础。我们提出了以下具体目标：1)确定干细胞移植的有效性是否取决于剂量或剂量分割；2)确定辐射后认知受损修复的最佳移植时间；3)确定移植干细胞的营养支持是否提供了修复放射性认知功能障碍的机制；4)确定移植干细胞的功能整合是否为修复放射性认知功能障碍提供了机制基础。这些特定目标的成功完成将使我们能够评估在临床上使用干细胞策略的潜在前景，并将阐明移植干细胞在改善辐射诱导的脑损伤中的有益作用的机制。 公共卫生相关性： 颅脑照射的衰弱认知副作用有很好的特征，但到目前为止，这个非常有问题的问题仍然知之甚少。每年大约有20万名患者接受全脑或部分脑照射，其中大约一半的脑肿瘤患者存活6个月以上。事实上，许多癌症患者现在的寿命更长(特别是儿童，他们的智商可能会下降3分/年)，导致认知缺陷，因此在停止有毒的癌症治疗方案后，设计出改善长期认知功能的方法变得越来越紧迫。虽然短期策略已经为改善认知损害提供了一些好处，但仍然没有令人满意的长期治疗方法来减少放射性脑损伤的进行性不良后遗症。因此，有很强的理由开展这项研究，评估一种基于干细胞的策略，作为逆转认知障碍和提高生活质量的潜在临床干预措施。总的来说，拟议的研究将为确定hNSCs在治疗放射性认知障碍方面的潜在临床效用提供基线和机械性数据，我们相信这些研究对美国和世界各地数百万癌症幸存者具有重要意义。

DESCRIPTION (provided by applicant): Numerous clinical studies have established the debilitating side effects of cancer therapies on cognition, and the major impact that these cognitive impairments have on quality of life. For those patients afflicted with primary and metastatic brain tumors, radiotherapy remains the only tenable option for impeding disease progression. Approximately 200,000 patients/yr receive whole or partial-brain irradiation in the U.S., and half of these patients survive over 6 months. To date, there are still no satisfactory long-term treatments for reducing the progressive adverse late effects of radiation-induced brain injury. Pediatric cases are of particular concern, as children treated with cranial radiotherapy can lose up to 3 IQ points/yr and often live long lives post-cancer. Even low doses of cranial irradiation that elicit minimal morphologic injury can result in variable degrees of cognitive dysfunction that manifest as impaired learning, memory, attention, concentration, and executive function. Therefore, with the exception of survival, cognitive impairment resulting from the clinical management of cancer may well be the most critical criterion for evaluating therapeutic outcome and long-term quality of life. Recent advances in treatment mean that cancer patients are surviving longer, making long-term function and quality of life a major priority. The foregoing highlights the urgent need to develop effective long-term strategies for preventing cognitive decline. The present proposal is focused on developing an innovative stem cell transplantation strategy. In our previous studies, we found that transplanted human embryonic (hESC) and neural stem cells (hNSC) rescue radiation-induced cognitive impairment in rats, providing the first evidence that stem cell strategies can be used effectively to ameliorate radiation-induced normal-tissue damage in the brain. Based on these significant and novel findings, we propose a comprehensive series of studies to investigate the translational potential and mechanistic basis underlying the capability of intrahippocampal transplantation of hNSCs to restore cognition in cranially irradiated rats. We propose the following Specific Aims: 1) determine if the effectiveness of stem cell transplantation depends on dose or dose fractionation, 2) determine the optimal post-irradiation transplantation time for restoration of impaired cognition, 3) determine whether trophic support derived from transplanted stem cells provides a mechanism for rescuing radiation-induced cognitive deficits, and 4) determine whether functional integration of grafted stem cells provides a mechanistic basis for the rescue of radiation-induced cognitive dysfunction. Successful completion of these specific aims will allow us to evaluate the potential promise of using stem cells strategies in the clinic, and will elucidate the mechanisms underlying the beneficial effects of transplanted stem cells in ameliorating radiation-induced brain injury. PUBLIC HEALTH RELEVANCE: The debilitating cognitive side effects of cranial irradiation are well characterized, but to date, this highly problematic issue remains poorly understood. Approximately 200,000 patients/yr receive whole or partial-brain irradiation, and roughly half of these brain tumor patients survive over 6 months. In fact, many cancer patients are now living longer (especially children who can lose up to 3 IQ points/yr) with debilitating cognitive deficits, so it is becoming more and more pressing to devise ways to improve long-term cognitive function after the cessation of toxic cancer treatment regimes. While short-term strategies have provided some benefit for ameliorating cognitive impairment, there are still no satisfactory long-term treatments for reducing the progressive adverse late effects of radiation-induced brain injury. Thus, there is a strong rationale for undertaking the research proposed in efforts to evaluate a stem cell based strategy as a potential clinical intervention for reversing cognitive impairments and improving quality of life. Collectively, the proposed studies will provide baseline and mechanistic data for determining the potential clinical utility of hNSCs in the treatment of radiation-induced cognitive disorders, studies we believe to be of major significance to millions of cancer survivors in the U.S. and worldwide.