The Mechanism of TGF-beta 1 in Adult Neurogenesis

巴克沃尔特博士是一名中风神经科医生和神经强化医生，接受过遗传学和分子生物学方面的培训。她对老年大脑对损伤的反应如何影响修复和功能恢复感兴趣。衰老与脑损伤后的恢复效果较差有关。这种下降的原因尚不清楚，但老化的大脑形成新神经元的能力下降可能是部分原因。申请人已经提供了初步数据，证明转化生长因子β -1 （tgf - β 1）对成人海马神经发生有明显的抑制作用，tgf - β 1是一种因衰老和损伤而增加的细胞因子。这些数据，以及已知的tgf - β对细胞周期的影响，使她提出了tgf - β 1直接作用于神经祖细胞以抑制海马神经发生的假设。因此，在老化的大脑中，特别是在受伤和衰老的大脑中，过多的tgf - β 1可能会抑制神经发生。她将确定tgf - β 1如何影响细胞周期和神经祖细胞的数量，这如何转化为更少的新神经元，以及这种影响的逆转是否会导致认知能力的提高。在这些研究的结论中，我们将对tgf - β 1抑制海马神经发生的机制有一个明显更好的理解。该申请还详细说明了精心设计的职业发展计划，包括与斯坦福大学其他实验室的丰富互动，参加研讨会和科学会议，监督学生和技术人员，以及神经科学和免疫学课程。巴克沃尔特博士拥有强大的机构支持，这将使她能够专注于这些研究，并将干扰降到最低。K08指导临床科学家职业发展奖将帮助Buckwalter博士从接受过遗传学培训的神经科医生转变为一名内科科学家，她完全有能力通过独立的研究者发起的资助，在自己的实验室里研究衰老的损伤反应。这项研究与公共卫生直接相关，因为美国有数百万人因创伤性脑损伤或中风而残疾。我们的数据显示，大脑中tgf - 1的升高，在所有这些疾病中都可以看到，会抑制我们大脑中细胞生长新神经元的能力。我们希望这个应用程序中的实验有一天能帮助我们设计出培育新脑细胞的策略，以取代那些因这些毁灭性疾病而失去的脑细胞。

DESCRIPTION (provided by applicant): Dr. Buckwalter is a stroke neurologist and neurointensivist with training in genetics and molecular biology. She is interested in how the aged brain's response to injury affects repair and functional recovery. Aging is associated with less effective recovery from brain injury. The reasons for this decline are unknown, but a reduced capacity of the aging brain to form new neurons may be in part responsible. The applicant has generated preliminary data that demonstrate a marked inhibition of adult hippocampal neurogenesis by transforming growth factor beta-1 (TGF-beta1), a cytokine that is increased by aging and injury. This data, and the known effect of TGF-beta on the cell cycle, led her to propose the hypothesis that TGF-beta1 acts directly on neural progenitor cells to inhibit hippocampal neurogenesis. Thus, too much TGF-beta1 in the aging brain, and especially in the injured and aged brain, may inhibit neurogenesis. She will determine how TGF-beta1 affects the cell cycle and number of neural progenitor cells, how this translates into fewer new neurons, and whether the reversal of this effect leads to cognitive improvement. At the conclusion of these studies, we will have a significantly better understanding of the mechanism by which TGF-beta1 inhibits hippocampal neurogenesis. This application also details a carefully thought out career development plan that includes rich interaction with other laboratories at Stanford, exposure to seminars and scientific meetings, supervision of students and technicians, and classes in neuroscience and immunology. Dr. Buckwalter has strong institutional support that will allow her to focus on these studies with minimal distractions. This K08 Mentored Clinical Scientist Career Development Award will facilitate Dr. Buckwalter's transition from a neurologist with training in genetics to a physician scientist who is fully competent to investigate the injury response in aging in her own laboratory through independent, investigator-initiated funding. This research is directly related to public health because millions of people in the US are living with disability due to traumatic brain injury or stroke. Our data shows that elevated brain TGF-beta 1, which is seen in all these diseases, inhibits our ability to grow new neurons from cells in our own brains. We hope that the experiments in this application will help us to someday design strategies to grow new brain cells to replace those lost to these devastating diseases.