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削弱性副作用，以及这些认知障碍对生活质量的主要影响。对于那些患有原发性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20万患者接受全脑或部分脑照射，一半的病人能存活6个月以上迄今为止，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晚期效应。儿科病例尤其令人担忧，因为接受颅放射治疗的儿童每年可损失高达3个IQ点，并且通常在癌症后寿命较长。即使是引起最小形态损伤的低剂量的颅骨照射也可导致不同程度的认知功能障碍，表现为学习、记忆、注意力、集中力和执行功能受损。因此，除了生存率之外，癌症临床管理导致的认知障碍可能是评估治疗结果和长期生活质量的最关键标准。治疗的最新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来预防认知能力下降。本提案的重点是开发一种创新的干细胞移植策略。在我们以前的研究中，我们发现移植的人胚胎干细胞（hESC）和神经干细胞（hNSC）挽救了大鼠辐射诱导的认知障碍，提供了干细胞策略可有效用于改善辐射诱导的正常组织损伤的第一个证据。基于这些重要的和新的发现，我们提出了一个全面的系列研究，以调查的翻译潜力和机制的基础上，海马内移植的hNSCs的能力，以恢复认知在颅脑照射大鼠。 我们提出以下具体目标：1）确定干细胞移植的有效性是否取决于剂量或剂量分级，2）确定恢复受损认知的最佳辐射后移植时间，3）确定来源于移植干细胞的营养支持是否提供了挽救辐射诱导的认知缺陷的机制，和4）确定移植干细胞的功能整合是否为挽救辐射诱导的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中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： 颅脑照射的认知副作用是很好的特点，但到目前为止，这个高度成问题的问题仍然知之甚少。每年约有20万例患者接受全脑或部分脑照射，这些脑肿瘤患者中约有一半存活超过6个月。事实上，许多癌症患者现在的寿命更长（特别是那些每年可以损失高达3个IQ点的儿童），他们的认知能力也越来越差，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。虽然短期策略对改善认知障碍提供了一些益处，但仍然没有令人满意的长期治疗方法来减少辐射诱导的脑损伤的进行性不良晚期效应。因此，有一个强有力的理由进行研究提出的努力，以评估干细胞为基础的战略作为一个潜在的临床干预逆转认知障碍和改善生活质量。总的来说，拟议的研究将提供基线和机制数据，用于确定hNSCs在治疗辐射诱导的认知障碍中的潜在临床效用，我们认为这些研究对美国和全球数百万癌症幸存者具有重大意义。

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.