Scooby...how about this:
First of all, go with HO. You can do a lot in that space in any scale, but with HO you can be up and going quicker since there is more stuff available in it.
Second, think of making a branch line. The branch could be on a "table" that runs from the middle of the space towards a wall.
Later, after you've gotten the branchline up and running, start planning on a mainline railroad that more-or-less follows the perimeter of the space. You can start off fairly small--say, just enough to interchange with the branch to start off with--and add on to it over time.
As the mainline increases in size, start thinking of where additional branches could be located. After you've built a second branch, you can keep yourself happily busy moving things from the first branch to the mainline, across the mainline to the second branch, then up into the second branch and back. Branchline engines would stay on the branches, while mainline engines would only work the mainline.
You have tremendous potential for variety with all that space if you use this scenario. For example, some branches could just be plain-old-branchlines that serve a few small towns and industries. A couple of branches could serve mines in a mountainous area, while others could be logging roads. You would even have plenty of space for one or two large cities that would be served by the mainline!
Another way to look at it is that you would be constructing individual layouts that are connected by a common mainline. By breaking it down like this, filling such a huge space shouldn't be overwhelming. Besides, you might just build a little bit and be perfectly happy. But then if you get bored with what you've got...you can always add more!
Gee...I wish I had that kind of space!
Here is a rough idea of what I'm talking about...